A History of Calcium Orthophosphates (Capo) From 1770S Till 1950

A History of Calcium Orthophosphates (CaPO4) from 1770s till 1950
SV Dorozhkin, Moscow, Russia

r 2016 Elsevier Inc. All rights reserved.
1 Introduction 1
2 General Definitions, Major Problems and Limitations 1
3 Investigations and Knowledge at the ‘Pre-CaPO4’ Time 3
4 Investigations and Knowledge on CaPO4 4
4.1 In the Eighteenth Century 4
4.2 In the Nineteenth Century 5
4.3 From 1900 till 1950 13
5 Early Publications on CaPO4 of the Geological Origin 17
6 Studies on CaPO4 in Living Organisms 20
6.1 Investigations Performed in the Eighteenth Century 20
6.2 Investigations Performed in the Nineteenth Century 21
6.3 Investigations Performed from 1900 till 1950 25
7 Early Attempts to Treat Various Diseases by CaPO4 27
8 CaPO4 as Bone Grafts 28
8.1 Artificial Grafts in the Nineteenth Century and Before 28
8.2 The Twentieth Century 30
9 Conclusions 32
References 32
1 Introduction
By virtue of abundance in the nature and presence in the living organisms, calcium orthophosphates (CaPO4) appear
to be the chemical compounds of a special interest in many fields of science, including geology, chemistry, biology, and
medicine [1,2]. As seen from Table 1, CaPO4 with the Ca/P ratio within 1.5–1.67 are called apatites (hydroxyapatite,
fluorapatite, and oxyapatite). As a mineral species, apatite was first recognized in 1786 by ‘the father of German geology’
Abraham Gottlob Werner (1750–1817) and named by him from the ancient Greek apatάo (apatao) – ‘to mislead’ or ‘to deceive’
because it had previously been mistaken for other minerals, such as beryl, tourmaline, chrysolite, amethyst, fluorite,
etc. [3]. Currently, apatite is the name for a group of minerals with the same crystallographic structure but with a diverse
chemical composition [4]. However, in this review, the term ‘apatite’ is referred to CaPO4 only and means CDHA, HA, FA, and OA
(Table 1).
As follows from the designation, all CaPO4 contain both calcium (Ca, atomic number 20) and phosphorus (P, atomic number
15) as the major constituencies. The history of both chemical elements is long. Namely, according to Wikipedia, the free
encyclopedia, calcium (from Latin calx, genitive calcis, meaning ‘lime’) compounds were known as early as the first century, when
the ancient Romans prepared lime as calcium oxide [5]. However, calcium sulfate (also known as plaster of Paris or lime plaster)
had been known much earlier: three statues were discovered in a buried pit at ’Ain Ghazal in Jordan those were sculpted with lime
plaster over armatures of reeds and twine. They were made in the pre-pottery Neolithic period, around 7200 BC. However, calcium
in a pure state was not isolated until 1808, when the famous British chemist and inventor Sir Humphry Davy (1778–1829)
electrolyzed a mixture of lime and mercuric oxide [6,7].
Phosphorus is a bit younger. The discovery of this element in a pure state (its name given from Greek mythology, Fosjόrος
meaning ‘light-bearer’ (Latin: Lucifer), referring to the ‘Morning Star,’ the planet Venus) is credited to the German merchant and
alchemist Hennig Brand (ca.1630–1710) from Hamburg in 1669, although other alchemists might have discovered phosphorus
around the same time. Brand experimented with urine, which contained considerable quantities of dissolved phosphates from the
normal metabolism [8]. As the matter stands, the earliest research publication, containing the word ‘phosphorus’ in the title
belongs to M. Krafft from Holland and was printed in 1677 in French Journal des Sçavans [9], which was the earliest academic
journal published in Europe. In 1680, a famous British natural philosopher, chemist, physicist, and inventor Robert Boyle (1627–
91) also published a study on phosphorus [10]. In addition, Boyle deposited another paper on the subject, but it was published
only in 1693, shortly after his death [11]. However, it was the famous French chemist Antoine Laurent Lavoisier (1743–94), who
recognized phosphorus as a chemical element in 1777. It turns out that phosphorus was the first element discovered since
antiquity [8].
Reference Module in Materials Science and Materials Engineering doi:10.1016/B978-0-12-803581-8.04089-3 1

2 A History of Calcium Orthophosphates (CaPO4) from 1770s till 1950
Table 1 Existing CaPO4 and their major properties [1,2]
Ca/P Compounds and their typical Chemical formula Solubility at Solubility at pH Stability range in
molar abbreviations 25 1C, log(Ks) 25 1C, g l 1 aqueous solutions at 25 1C
ratio
0.5 Monocalcium phosphate monohydrate Ca(H2PO4)2 H2O 1.14 B18 0.0–2.0

(MCPM)
0.5 Monocalcium phosphate anhydrous Ca(H2PO4)2 1.14 B17 c
(MCPA or MCP)
1.0 Dicalcium phosphate dihydrate (DCPD), CaHPO4 2H2O 6.59 B0.088 2.0–6.0
mineral brushite
1.0 Dicalcium phosphate anhydrous (DCPA CaHPO4 6.90 B0.048 c
or DCP), mineral monetite

1.33 Octacalcium phosphate (OCP) Ca8(HPO4)2(PO4)4 5H2O 96.6 B0.0081 5.5–7.0
1.5 a-Tricalcium phosphate (a-TCP) a-Ca3(PO4)2 25.5 B0.0025 a
1.5 b-Tricalcium phosphate (b-TCP) b-Ca3(PO4)2 28.9 B0.0005 a
1.2–2.2 Amorphous calcium phosphates (ACP) CaxHy(PO4)z nH2O, n ¼3–4.5; b b

B5–12d
15–20% H2O
1.5–1.67 Calcium-deficient hydroxyapatite (CDHA Ca10x(HPO4)x(PO4)6x(OH)2x B85 B0.0094 6.5–9.5
or Ca-def HA)e (0oxo1)
1.67 Hydroxyapatite (HA, HAp or OHAp) Ca10(PO4)6(OH)2 116.8 B0.0003 9.5–12
1.67 Fluorapatite (FA or FAp) Ca10(PO4)6F2 120.0 B0.0002 7–12
1.67 Oxyapatite (OA, OAp or OXA)f, mineral Ca10(PO4)6O B69 B0.087 a
voelckerite
2.0 Tetracalcium phosphate (TTCP or Ca4(PO4)2O 38–44 B0.0007 a
TetCP), mineral hilgenstockite

a
These compounds cannot be precipitated from aqueous solutions.
b
Cannot be measured precisely. However, the following values were found: 25.770.1 (pH¼ 7.40), 29.970.1 (pH ¼6.00), 32.770.1 (pH ¼ 5.28). The comparative extent of
dissolution in acidic buffer is: ACPca-TCPcb-TCP4CDHAcHA4FA.
c
Stable at temperatures above 100 1C.
d
Always metastable.
e
Occasionally, it is called ‘precipitated HA (PHA).’
f
Existence of OA remains questionable.
2 General Definitions, Major Problems and Limitations
To begin with, one must define the subject and outline the problems. According to Wikipedia: ‘History (from Greek ἱstοrίa –
historia, meaning ‘inquiry, knowledge acquired by investigation’) is the discovery, collection, organization, and presentation of
information about past events. It is a field of research which uses a narrative to examine and analyze the sequence of events, and it
sometimes attempts to investigate objectively the patterns of cause and effect that determine events. The task of historical discourse
is to identify the sources which can most usefully contribute to the production of accurate accounts of past’ [12]. Therefore, all
written below should be considered as a set of the chronological narratives on various aspects of CaPO4, in which extensive
quotations from old publications appear to be the historical facts and data suitable for analysis and reconsideration from the
modern points of view.
Unfortunately, due to the substantial difficulties with accessing to the scientific literature published in the first half of the
nineteenth century and before, the requirement ‘to identify the sources’ meets serious problems. In addition, that time, both the
scientific concepts and the presentation ways were rather different from the modern ones, while the chemical formulae had not
been introduced yet. More to the point, scientific journals were rare and just a few of them are currently available in the electronic
form. To complicate things further, numerous old journals have been discontinued, merged and/or renamed, which strongly
complicates accessing to the papers published in those journals. Luckily, Google Inc. has scanned a great number of old books as a
part of its project to make the world’s books discoverable online. This timely project by Google combined with the power of the
modern electronic databases of scientific publications allows reconstructing the major historical milestones on CaPO4, which was
often impossible for earlier review writers. For example, a paper of 1994 by Driskell entitled: “Early history of calcium phosphate
materials and coatings” [13] started with the classical publication of 1920 by Albee assisted by Morrison [14]. In 1999, Shackelford
published a paper: “Bioceramics – an historical perspective” [15], in which the same publication by Albee and Morrison [14] was
mentioned as the earliest reference. The same is valid for the historical papers by Hulbert et al. [16,17] and Shepperd [18]. Thus, it
might create a false impression that CaPO4 were unknown before 1920. Certainly, this is not the case; nevertheless, the precise
sequence of the scientific events happened in the first half of the nineteenth century still remains poorly restorable, while the
correct historical time scale of even earlier scientific events remains almost irrecoverable. This is mainly due to a lack of the citation
A History of Calcium Orthophosphates (CaPO4) from 1770s till 1950 3
practice existed in the scientific literature published that time. Besides, even nowadays, for the entire eighteenth century and
approximately the first quarter of the nineteenth century, only scientific books digitalized by Google are easily accessible. Just a few
journal publications devoted to the subject published before B1820s have been found. Nevertheless, in no case this means that
they do not exist; presumably, either they have not been scanned yet (especially, this might be valid for the discontinued journals)
or an access to the scanned versions is restricted to a limited amount of subscribers only. Therefore, the historical narrative of the
findings and discoveries of the eighteenth century is based dominantly on the available books, the annals of the nineteenth
century are based on both the available books and a limited number of journal papers, while the chronicle of the twentieth century
is based on the journal publications only. Here one should also stress that starting from the second half of the nineteenth century
the detailed description of every publication on the subject becomes impossible due to continuous increasing amount of them.
Furthermore, since the end of 1910s, even mentioning all and sundry publications on the subject becomes impossible either (the
quantity with moderate novelty breeds ignoring). Therefore, for the twentieth century, the milestone studies have been
included only.
3 Investigations and Knowledge at the ‘Pre-CaPO4’ Time
Prior examination of issues let me briefly report on the earliest scientific publications on bones, teeth, and other types of calcified
tissues of mammals, which are the main sources of CaPO4 of the biological origin. Since in those early days Latin was the major
scientific language, I am forced to confine myself by a limited amount of English-language publications only.
According to the second earliest but the world’s longest-running scientific journal Philosophical Transactions (published
in UK), the priority in journal publications on investigations of bones and teeth belongs to the famous Dutch tradesman and
scientist Antonie Philips van Leeuwenhoek (1632–1723) from Delft. He is best known for his work on the improvement of a
microscope and is often considered as ‘the father of microbiology.’ Therefore, within 1674–95, van Leeuwenhoek
published several letters devoted to microscopic investigations of bones and teeth [19–23]. Namely, he wrote (please, note the old-
fashioned using a long, medial or descending letter ‘ſ,’ which is a form of the minuscule letter ‘s’ formerly used where ‘s’
occurred in the middle or at the beginning of a word) [19]: “I thought likewiſe, I ſaw then alſo, that that Bone conſiſted
of united Globuls. Afterwards, I viewed the Shinbone of a Calf, in which I found ſeveral little holes, paſſing from without inwards;
and I then imagined, that this Bone had divers ſmall pipes going longways:” (p. 125). Today these small pipes are known as
Haversian canals, named after the British physician Clopton Havers (1657–1702), who did the pioneering research on the
microstructure of bones and teeth, which were published as a book in 1691 [24]. Let me continue citing [19]: “But I have
ſince obſerved the Tooth of a Cow and I found it made up of tranſparent Globuls which I can ſee very perfectly. The ſame I have
obſerved in Ivory or Elephants-Teeth. And having ſeen this ſeveral times, I doubt no longer but that all white Bones do conſiſt of
tranſparent Globuls” (p. 125). Obviously, this was the first recognition of the fact, that bones and teeth of mammals consist of
small units (currently we call them crystals) with a transparent nature. Indeed, single crystals of all known CaPO4 (Table 1) are
transparent.
Simultaneously, other researchers tried to measure the physical properties and establish the chemical composition of
various calcified tissues (both normal and pathological) of humans. For example, let me cite a summary of the experiments
performed by the British physician and chemist Frederick Slare (1648–1727) from a publication of 1684 [25]: “Several Stones of
the Bladder and Kidnies were diſtill’d, all afforded volatile urinous Salts ; which Ferment upon any Acids. Bones were diſtill’d and found
to be of agreeable Principles. Calculi examined Hydroſtatically, were found in proportion to their Bulk of water as 5 to 4. We weigh’d
Bones Hydroſtatically and found them twice as heavy as their Bulk of water. Bones not eaſily wrought on by common Acids, only by
nitrous ones and that without Ebullition” (p. 532). Therefore, scientists dissolved biologically formed CaPO4 in acids as far back
as 1684.
Shortly before a discovery of the CaPO4 nature of bones (the next section), Hérissant (I have found three people with this
family name: Jean Thomas Hérissant (1704–72), his son Louis Antoine Prosper Hérissant (1745–69) and François-David Hér-
issant (1714–73)) and a Swiss anatomist, physiologist, naturalist, and poet Albrecht von Haller (1708–77), examined a phe-
nomenon that even the weakest acids had the power of softening bones. Namely, according to Fourcroy [26], that study was
reported in 1758 (therefore, Louis Antoine Prosper Hérissant should be excluded) and Hérissant “thought he had found in the
nitric acid (with which he ſoftened the bones which he ſoaked in it, by diſſolving their earth, which he believed to be cretaceous,
without affecting their membraneous cellular part) a means of inſulating the two conſtituent matters of theſe organs. Haller has
verified this ſoftening of the bones even by the acetous acid and lemon juice: he ſuſpected that in the ſoftening of the bones by the
effect of diſeaſes, there exiſted an acid which thus corroded them. All the chemiſts have afterwards obſerved that a ſolution of
bones in an acid precipitated by alkali affords a ſeemingly earthy matter, which does not poſſeſs the property of becoming quick-
lime by calcination” (p. 388).
To conclude this part, one can see that the aforementioned few examples clearly demonstrate a scientific importance of the ‘pre-
CaPO4’ epoch, which, ideally, should be investigated in more details. Undoubtedly, one must appreciate the important obser-
vations and discoveries, made by those early researchers-predecessors.
4 Investigations and Knowledge on CaPO4
4.1 In the Eighteenth Century

According to the available literature, the history of CaPO4 started in 1769 and was associated with names of the famous Swedish
chemist and metallurgist Johan Gottlieb Gahn (1745–1818) and the famous German–Swedish pharmaceutical chemist Carl
Wilhelm Scheele (1742–86). Namely, in 1881, Roscoe and Schorlemmer [27] published the following statement: “Gahn, in 1769,
discovered the existence of calcium phosphate in bones, but it was not until this fact was published by Scheele in 1771 that
phosphorus was obtained from bone-ash, which has from that time invariably served for its preparation” (p. 458). In 1843, a
Scottish chemist and mineralogist Thomas Thomson (1773–1852), whose writings contributed to the early spread of Dalton’s
atomic theory, wrote the following [28]: “In some of the earlier systems of chemistry, the earth of bones is considered as a substance
sui generis, and ranked among the earths. About the year 1768, Assessor Gahn of Fahlun discovered that this supposed earth
consisted chiefly of phosphate of lime. Scheele, in his experiments on fluor spar, published in 1771, mentions, when giving an
account of the action of phosphoric acid on fluor spar, that it had been lately discovered that the earth of bones was phosphate of
lime” (p. 235). The Scheele’s experiments with fluorspar are available in literature [29].
Furthermore, let me quote a publication of 1777 [30] (again, pay attention to the old-fashioned using a letter ‘ſ’ instead of ‘s’): “I
have only been informed of this diſcovery, by the Gazette, Salutaire de Bouillon, October, 1775. It is there ſaid, that Mr. Henry Gahn, a
phyſician at Stockholm, has communicated a proceſs for extracting from bones the ſaline matter in question; and that
Mr. Scheele had aſcertained, that the earth of animals was compoſed of a calcareous ſubſtance united with the phoſphoric acid.
This diſcovery, continues the author of the article of the Gazette, belongs to Mr. Gahn, and has been confirmed by later experiments”
(p. 383). Presumably, the latter citation might be considered as one of the earliest mentioning on calcium phosphates in the history.
The earliest accessible description on how Scheele discovered the chemical composition of bones was given by Fourcroy in
1804 [26]: “After having, like Heriſſant, diſſolved bones in the nitric acid, he filtrated the liquor, and aſcertained that, though
always acid, even when ſaturated with all that it could diſſolve of bone, it precipitated ſulphate of lime by the addition of
concentrated ſulphuric acid ; and that after this precipitation, the ſolution drawn off clear, and evaporated in a retort, afforded
volatilized nitric acid, and left phoſphoric acid, which was fuſed into glaſs by the action of a ſufficient heat. He concluded from
this experiment that the nitric acid diſſolved the phoſphate of lime, the baſe of the bones ; that the ſolution in this acid was a
mixture of calcareous nitrate and of phoſphoric acid ; that when the firſt was decompoſed by the ſulphuric acid, and the
precipitated ſulphate of lime ſeparated from it, there remained only a mixture of the two acids, the phoſphoric and the nitric, and
that this latter mixture, when heated, diſengaged volatile nitric acid, whilſt the fixed phoſphoric acid remained at the bottom of the
retort” (pp. 388–389). Even more than 200 years afterwards, we can add nothing to improve this description. This is an example
how the genius could do!
Simultaneously, the presence of orthophosphates was discovered in blood serum, which follows from a publication of 1770
[31]: “The ſerum conſiſts chemically of a coagulable matter, and water in which common ſal ammoniac and phoſphoric
ammoniac, and generally common ſalt, and frequently ſelenites, and, fixed ammoniac, are diſſolved; …” (p. 309). Obviously,
‘phoſphoric ammoniac’ means ammonium orthophosphate.
Further, according to Shepperd [18], the famous German chemist Martin Heinrich Klaproth (1743–1817) and the famous French
chemist Joseph-Louis Proust (1754–1826) also contributed to CaPO4. Unfortunately, Shepperd has not provided any references to
the publications by those great chemists. Nevertheless, a search performed among the Google books has given some results. For
example, a short extract from a letter by M. Klaproth was published in 1788 [32], which started with the following words: “Monsieur,
Je viens d’analyſer l’apatit de M. Verner (I). J’en ai retiré de la terre calcaire & de l’acide phoſphorique” (p. 313). In addition, in a
French book of 1790 [33], one can find a subchapter entitled “Apatite. Phosphate de Chaux.” which is started from the following
sentence: “C’est Mr. Klaproth , qui à découvert le premier cette combinaison de la terre calcaire avec l’acide phosphorique” (p. 363).
Further, “Mr. Proust dans une Lettre à Mr. d’Arcet a donné l’Analyse de cette pierre, qui est une combinaison de la terre calcaire avec
l’acide phosphorique” (p. 366). Thus, by that time, apatite was already recognized as a calcium phosphate, which is also confirmed
by a German book of 1789 [34], in which “Apatit” was called “die Phosphorsaure mit Kalkerde” (p. 2).
More to the point, according to a study, submitted on December 20, 1785 [35], the production process of orthophosphoric
acid by decomposition of calcined bones in sulfuric acid was already known. This is how it was described by Lavoisier in 1790
[36]: “The bones of adult animals being calcined to whiteneſs, are pounded, and paſſed through a fine ſilk ſiewe; pour upon the
fine powder a quantity of dilute ſulphuric acid, leſs than is ſufficient for diſſolving the whole. This acid unites with the calcareous
earth of the bones into a ſulphat of lime, and the phoſphoric acid remains free in the liquor” (p. 205). Further, the production
process of white phosphorus has been described [36]: “The liquid is decanted off, and the reſiduum waſhed with boiling water;
this water which has been uſed to waſh out the adhering acid is joined with what was before decanted off, and the whole is
gradually evaporated; the diſſolved ſulphat of lime criſtallizes in form of ſilky threads, which are removed, and by continuing the
evaporation we procure the phoſphoric acid under the appearance of a white pellucid glaſs. When this is powdered, and mixed
with one third its weight of charcoal, we procure very pure phoſphorus by ſublimation” (p. 206).
In 1790, two French pharmacists and chemists Bertrand Pelletier (1761–97) and Louis Donadei published identical papers
[37,38] (the earliest example of redundant publications?) on the results of the extensive investigations with CaPO4 including their
treatment by various acids. However, the last decade of the eighteenth century is going to be remembered due to the very extensive
investigations on CaPO4 performed by two famous French chemists Antoine François, comte de Fourcroy (1755–1809) and Nicolas
Louis Vauquelin (1763–1829), who, among other accomplishments, discovered an existence of acidic CaPO4, currently known as
MCPM, MCPA, DCPD, and DCPA (Table 1). For example, let me cite a Fourcroy’s book of 1789 [39]: “Phoſphoric acid, poured into
lime-water, precipitates from it a ſcarce ſoluble ſalt, which does not efferveſce with acids, – is decompoſed by mineral acids, but proof
againſt the attacks of cauſtic alkalis. This ſalt is of the ſame nature with the baſe of bones. – An exceſs of phoſphoric acid renders
calcareous phoſphate ſoluble in water; but magneſia, lime, cauſtic fixed alkalis, and even ammoniac, by carrying off from it the exceſs
of acid, precipitate the neutral ſalt. Calcareous phoſphate is not decompoſable by caustic alkalis, but carbonates of potaſh and ſoda
decompoſe it. The ſolid matter of bones conſiſts of phoſphate ſuperſaturated with lime” (p. 248). Here we read the correct chemical
description of CDHA precipitation from H3PO4 and Ca(OH)2, followed by CDHA transformation into soluble MCPM in the
presence of an excess of H3PO4, which is again transformed into insoluble CDHA by addition of basic compounds MgO, CaO, KOH,
NaOH, and NH4OH. Moreover, the last sentence means, that the amount of CaO in bones exceeds the stoichiometry of ortho-
phosphates; therefore, that was the earliest indirect observation of the apatitic (Ca/P41.5) composition of bones.
Furthermore, in his later book of 1804 [40] Fourcroy wrote: “A FEW years ago this ſalt, which I here denominate the acid
phoſphate of lime, was unknown. Scheele very properly remarked that the ſaline earth of bones was diſſolved by an acid in human
urine, but he did not obſerve that this union between phoſphoric acid and the bony phoſphate, makes a kind of permanent and
particular ſalt different from the latter. It was in the year 1795, the third year of the Republic, that I diſcovered it, with Citizen
Vauquelin, in a connected ſeries of experiments upon bony matters; wherein we proved that the calcareous phoſphate which
conſtitutes the ſolid baſe, is only in part decompoſable by acids, and that the portion of phoſphoric acid which is ſeparated, retains
in ſolution phoſphate of lime, which it then defends from all ſubſequent alteration by other acids” (p. 347). The aforementioned
is confirmed by an encyclopedia published in 1816 [41]: “Super-PHOSPHAT OF LIME was diſcovered in 1795, by Fourcroy and
Vauquelin. It had indeed been often formed before, but chemiſts had neglected to examine it” (p. 458). Thus, the term ‘super-
phosphate’ has been known since, at least, 1795 and initially it meant calcium phosphates containing an excess (or super quantity)
of phosphoric acid. Besides, in the same publication Fourcroy mentioned other contributors to early studies on CaPO4 [40]:
“Citizens Nicholas of Nancy, Pelletrier, Berniard, Bullion, in France; Weſtrumb, and ſeveral chemiſts in Germany; Bonvioſin, at
Turin; Tenant, Pearſon, and ſome others in England, multiplied their inquiries and experiments” (p. 337). Thus, one can notice
that in the end of the eighteenth century, the subject of CaPO4 was extensively investigated by a number of researchers in several
countries of the Western Europe.
Finally, it is important to quote a page from an agricultural chemistry book, published in 1795 [42]: “PHOSPHAT OF LIME Is
contained in animal matters, such as bones, urine, shells, &c. &c. in some sorts of limestone, and in vegetable substances,
particularly in the gluten, or vegeto-animal matter of wheat or other grain. It is a saline compound very insoluble. There is reason
to believe, a very considerable proportion of this nearly insoluble salt is contained in most fertile soils, especially those that have
been long under cultivation. It is not to be decomposed by pure alkalis ; but this may be effected by mild vegetable and mineral
alkalis, on the principle of the double electrive attractions ; in which case, carbonate of lime (or chalk) will be precipitated, and
phosphoric acid will join with the alkali, and form phosphat of potash, or phosphat of soda, according to the alkali applied. These
alkaline phosphates will be found to promote vegetation in a very great degree : the substances of which they are composed, viz.
alkaline salts and phosphoric acid, are found in the ashes of most vegetables” (p. 75).
To conclude the 1700s, one should recognize that the correct basic knowledge on CaPO4 became available by the end of the
eighteenth century.
4.2 In the Nineteenth Century

For the nineteenth century, both scientific books and a limited amount of journal publications are available; however, for the first
half of the nineteenth century, the quantity of journal publications was very small. Nevertheless, according to the available
literature, one can claim on a real explosion of the scientific knowledge on CaPO4 in the nineteenth century. For example, in 1804,
Fourcroy stated that the presence of water in acidic CaPO4 was already known (again, pay attention to the old-fashioned using a
letter ‘ſ’ instead of ‘s’) [40]: “The acid phoſphate of lime contains a remarkable quantity of water: the cryſtallization immediately
ſoftens and becomes liquefied by the fire” (p. 349). The chemical compositions of both neutral and acidic CaPO4 were described
as follows [40]: “100 parts of phoſphate of lime contain, according to the analyſis of Citizens Fourcroy and Vauquelin,
Phoſphoric acid 41
Lime 59” (p. 346)
and “An accurate analyſis of this ſalt affords the following proportions of component parts,
Lime 45
Phoſphoric acid 54” (p. 351)
Unfortunately, it is impossible to establish the real meaning of all numerical values. Nevertheless, if we consider the first
compound as the stoichiometric HA (Ca/P ¼ 1.67), simple calculations using the proportion rules will give Ca/P ¼ 0.96 for the
acidic phosphate of lime and if we consider the first compound as TCP (Ca/P ¼ 1.50), the similar calculations will give Ca/P¼ 0.86
for the acidic phosphate of lime. In both cases, the calculated Ca/P ratios appear to be close to those in DCPD and DCPA. Taking
into the consideration that the ‘acid phoſphate of lime contains a remarkable quantity of water,’ one can conclude that Fourcroy
prepared DCPD by 1804. Finally, one more citation from the Fourcroy’s book [40]: “The phoſphate of lime is extremely difficult to
fuse; nevertheleſs, by ſtrong fire, ſuch as that of a glaſs-house, it ſoftens and acquires a ſemi-tranſparence like the grain of
porcelain” (p. 341). Thus, calcium phosphate ceramics was prepared by 1804.
Knowledge on acidic CaPO4 was further developed in 1805 [43]: “Acid Phosphate of Lime is formed either by taking away a part
of the base by sulphuric, nitric, or muriatic acid, or by superadding phosphoric acid to the last described phosphate” (p. 195) and
in 1806 [44]: “In this way were distinguished among the salts two combinations, one neutral, and one with an excess of acid; and
these were supposed to be determinate, as in sulphate and super-sulphate of potassa, or the phosphate and super-phosphate of
lime” (p. 38). In 1807, a detailed preparation technique of super-phosphate of lime was described as follows [45]: “This ſuper-
phosphat of lime is prepared with moſt accuracy by digesting phoſphat of lime in phoſphoric acid till it is ſaturated. This ſolution
yields the ſalt by evaporation in the form of ſmall ſhining seales or filaments which have almost a gelatinous conſiſtence, and a
very ſour taſte” (p. 222). Obviously, this was the earliest description of MCPM preparation; however, an admixture of MCPA was
possible due to a partial dehydration at the evaporation stage.
More precise information on acidic CaPO4 became available by 1819 [46]: “XI. Biphosphate of Lime. – This salt may be formed
by digesting phosphate of lime in phosphoric acid, dissolved in hot water” (p. 327). “XII. Quadriphosphate of Lime. – Glassy
Phosphoric Acid of the Apothecaries. – This salt may be formed by digesting, for some time, finely powdered phosphate of lime in a
quantity of sulphuric acid, sufficient to saturate all the lime of the phosphate, and afterwards diluting the mixture with a sufficient
quantity of water, and filtering. Sulphate of lime remains on the filter, and a liquid quadriphosphate passes through” (pp. 327–
328). Presumably, aqueous solutions of DCPD and MCPM, respectively, were prepared; therefore, one can claim that MCPM and
DCPD were differentiated by 1819. Furthermore: “XIII. Subphosphate of Lime. – This salt occurs native under the names of apatite or
asparagus stone” (p. 328). Since the prefix ‘sub’ means ‘incomplete,’ one can claim that a shortage of orthophosphate ions in
apatites (if compared with phosphate of lime) was confirmed.
Various preparation processes of a pure CaPO4 currently known as CDHA were developed by 1807 [45]: “PHOSPHATE OF LIME
may be obtained quite pure either by ſaturating the pure acid with marble and then evaporating; or by waſhing bone-aſh with hot
water to diſſolve out any ſoluble ſalt which it may contain; then adding a little acetous or dilute muriatic acid till the efferveſcence
ceaſes to engage the carbonat of lime which it contains, and again thoroughly edulcorating. Phoſphat of lime is produced
alſo by double decompoſition, on dropping a ſolution of any phoſphated alkali into any ſoluble calcareous ſolution that has not any
great exceſs of acid. Vauquelin alſo found that on boiling phoſphat of ſoda with wet and newly precipitated carbonat of lime, the
ſame reſult took place, and carbonate of ſoda with phoſphate of lime were produced” (p. 221). One can see that some of these
processes are still used to produce chemically pure CDHA. In the fourth edition of Encyclopædia Britannica (1810), applications of
CaPO4 were described as follows [47]: “The phoſphate of lime is of great importance in chemiſtry, for the purpoſe of extracting
phoſphoric acid, to be decompoſed to obtain phoſphorus. It is also employed for making cupels, for poliſhing metals and precious
ſtones, and for removing ſpots of greaſу from linen, paper, and ſilk. It is uſed in medicine as a remedy for rickets, to correct the
ſuppoſed effects of acids in ſoftening the bones” (p. 585). Although it is slightly beyond the subject, one should mention, that
calcium orthophosphite (Ca3(PO3)2) with trivalent P was also mentioned in that edition of Encyclopædia Britannica, as “phoſphite
of lime” (p. 586).
In 1813, the following preparation route of CDHA was described [48]: “Phosphate of lime, proper. As this salt constitutes the
basis of bones, it is not necessary to prepare it artificially. It may be obtained in a state of purity by the following process:
Calcine the bones to whiteness, reduce them to powder, and wash them repeatedly with water, to separate several
soluble salts, which are present. Dissolve the whole in muriatic acid, and precipitate by means of ammonia. The precipitate, when
well washed and dried, is pure phosphate of lime.” Obviously, quite pure CDHA with Mg and Sr as minor admixtures was
prepared by this technique. Further, the known properties of CDHA were described as follows [48]: “Phosphate of lime, thus
prepared, is always in the state of white powder ; but it is found native in regular crystals. In that state it is known by
the name apatite. The primitive form of its crystals is, according to Haüy, the regular six-sized prism ; and the primitive form of its
integraut particles is a three-sided prism, whose bases are equilateral triangles ; but it very often assumes other forms.” Here we can
see the correct description of the crystal habitus of apatites. Further: “It is destitute of taste, insoluble of water, and not liable to be
altered by exposure to the air. It may be exposed to a strong heat without undergoing any change ; but in a very violent heat it
becomes soft, and is converted into a white semitransparent enamel, or rather porcelain. Sulphuric, nitric, muriatic, fluoric, and
several vegetable acids, are capable of decomposing phosphate of lime ; but the decomposition is only partial. This
salt is employed in making cupels ; and almost solely in extracting phosphorus. It is also used, occasionally, as a medicine in
rickets” [48].
In 1819, the following was written by Bache [46]: “5. According to an analysis by Berzelius, calculated in numbers, in which the
equivalent number for lime is assumed, phosphate of lime is composed of
Phosphoric acid 34 3 –
Lime 29 0 – one atom;
so that it appears that the composition of this salt cannot be reconciled with the atomic theory” (p. 327). Here, there was the
earliest mentioning of the terms ‘atom’ and ‘atomic theory’ for CaPO4 subject. In 1821, the aforementioned Thomson, wrote the
following [49]: “We see that the weights of the atom of phosphoric acid and of lime are exactly equal. Hence neutral phosphate of
lime is composed of
Phosphoric acid 50
Lime 50
_____
100” (p. 12)
Although the aforementioned numeric values best correspond to the OCP composition, the term ‘an atom’ undoubtedly means
either ‘a molecule’ or ‘a mole.’
In 1823, W. Henry described the following compounds containing calcium and phosphorus [50]: phosphuret of lime obtained by
passing phosphorus over red-hot lime (p. 565), which, obviously, was calcium phosphide (Ca3P2). It “has the remarkable property of
decomposing water and the water afterwards contains phosphite, or hypophosphite, not phosphate of lime. Drop a small piece of it
into a wine-glass of water, and in a short time bubbles of phosphuretted hydrogen gas will be produced; which, rising to the surface, will
take fire, and explode” (p. 566), followed by references to two publications written by the famous French chemist and physicist Joseph
Louis Gay-Lussac (1778–1850), to whom this discovery was credited. Obviously, the ‘phosphuretted hydrogen gas’ was a mixture of
PH3, P2H4, and more complicated PH-compounds. Then, W. Henry described phosphate of lime [50], which “is constituted, according to
Mr. Dalton’s experiments, of 49 acid þ 51 lime, proportions which authorize us to consider phosphate of lime as consisting of 1 atom of
acid¼ 28, þ 1 atom of base¼ 28, the compound atom being 56” (pp. 566–567). Here, the term ‘atom’ was used again. In addition, this
is an evidence that the famous English chemist, meteorologist and physicist John Dalton (1766–1844), who is best known for his
pioneering work in the development of modern atomic theory, as well as his research into color blindness (sometimes referred to as
daltonism, in his honor), also contributed to CaPO4. Afterwards, other CaPO4 were mentioned as [50]: “Bi-phosphate of lime may be
formed by digesting phosphate of lime with a quantity of phosphoric acid equivalent to that already engaged in the salt” (p. 567) –
obviously, it was DCPD. “Tri-phosphate of lime. – This salt, according to Mr. Dalton may be formed by adding pure phosphoric acid to
lime water, till a commencement of precipitation appears, when the solution must be cleared by a drop or two of acid. If the solution be
evaporated to dryness at a moderate heat, and then dissolved in water again, simple phosphate of lime remains, and a quadri-phosphate
exists in the solution” (p. 567) – unfortunately, this description does not allow to identify CaPO4. They might be DCPD (in solution)
and DCPA (evaporated to dryness at a moderate heat) or OCP (in solution) and either ACP or CDHA (evaporated to dryness at a
moderate heat). “Quadri-phosphate of lime. – If 100 parts of phosphate of lime be digested for 24 h with 87 parts of sulphuric acid, diluted
with a sufficient quantity of water, and be then filtered, the liquid which passes through contains the whole of the phosphoric acid, with
only one-fourth of the lime which existed in the original salt … The dissolved salt is therefore a compound of 1 atom of lime¼ 28 þ 4
atoms of acid¼ 112. When evaporated it forms, on cooling, pearly scales, which have an acid taste, and dissolve readily in water, giving a
solution of the sp. gr. 1,44” (p. 567) – obviously, this was MCPM with a possible admixture of MCPA formed after evaporation.
Although the meaning of the statement “1 atom of lime¼ 28 þ 4 atoms of acid¼ 112” remains unclear, one may guess that the
numerical values 28 and 112 should be a kind of molar masses. Indeed, 28 is 50% of the molar mass of CaO, i.e., this is a gram
equivalent (synonym: an equivalent weight). According to Wikipedia, the equivalent weights were established by 1777 [51]; therefore,
this suggestion sounds reasonable. Finally, W. Henry [50] mentioned “Octo-phosphate of lime. – Mr. Dalton is of opinion that a
compound of 8 atoms of acid and 1 atom of lime is the true result of the process described under the last head ; and that a compound of
as many as 12 atoms of acid with one of lime may exist, forming a dodecaphosphate” (p. 567). Such super-acidic CaPO4 are currently
unknown; moreover, they were excluded from the books published in 1828 [52] and 1829 [53]. Presumably, chemists quickly found a
mistake. In addition, in the latter book one can read the following [53]: “The biphosphate of lime may be prepared by adding one atom of
phosphoric acid to one atom of the phosphate of lime” (p. 252). Since the term ‘an atom’ undoubtedly means either ‘a molecule’ or ‘a
mole,’ the correct chemical understanding of the stoichiometry of DCPD preparation from H3PO4 and TCP was achieved by 1829.
By 1827, a German mineralogist Gustav Rose (1798–1873) established the correct understanding of the chemical composition
of apatites, in which there is one ‘atom’ of either the chloride or the fluoride of calcium, or mixtures thereof, bound to three ‘atoms’
of CaPO4 [54]: “Nennen wir die erstern Chlorapatite, die letztern Fluoroapatite” (p. 196). Rose was of the opinion that chloride
and fluoride are isomorphous and could replace each other in the apatites. Since the full text of this publication is not accessible,
let me quote a publication of 1859, co-authored by the famous French chemist Henri Étienne Sainte-Claire Deville (1818–81)
[55]: “The singular composition of apatite, first determined by M. Gustav Rose in 1827, shows that it is a definite compound of
chloride and fluoride of calcium with phosphate of lime” (p. 128). In 1832, a chemical term “tribasic phosphate of lime” (p. 90),
which fully corresponds to both a-TCP and b-TCP, was mentioned for the first time [56].
Coincidently, the famous German chemist Eilhard Mitscherlich (1794–1863), who was both a learner and a friend of J.J.
Berzelius and who is best remembered today for his law of isomorphism (1819), also worked in this area. To prove this, let me cite
an introduction from a paper of 1833, written by the Scottish chemist Thomas Graham (1805–69), clearly demonstrating the
established knowledge on phosphates and arsenates by that time [57]: “No classes of salts have more liberally rewarded inves-
tigation than the arseniates and the phosphates. Witness the discovery of the extraordinary phosphates of lime by Berzelius ; the
observation of the identity of form of the corresponding arseniates and phosphates by Mitscherlich, and the doctrine of iso-
morphism to which that observation led ; the discovery by the same chemist of two biphosphates of soda, agreeing in composition
but differing in form ; and lastly, the discovery of the pyrophosphates by my friend and townsman Mr. Clark. Much, however, still
remains to be done to complete the history of these interesting salts” (p. 253). In addition, various modifications of phosphoric
acid, currently known as orthophosphoric, pyrophosphoric and metaphosphoric acids were already known. On p. 281 of his
paper, Graham called them as “a terphosphate, a biphosphate, and phosphate of water,” respectively [57].
Concerning chemical formulae of CaPO4, the earliest ones I have managed to find were discovered in the aforementioned
paper of 1833 by Graham [57] as and (p. 265). Another type of the chemical formulae with struck out phosphorus
was published in 1844 by Mitscherlich [58] as 2.Ca2P and 5.Ca2P (p. 69a). Furthermore, a combination of both styles with dots
above the element’s symbols as in Ref. [57] and striking out phosphorus as in Ref. [58] (additionally, chlorine was written as Cl
and fluorine was written as F) was also used [59]. Even such a complicated way of writing with dots, striking out and mathematical
fractions as was used on page 399 of Ref. [60] to describe the chemical composition of apatite. One can see that
initially neither hydrogen, nor oxygen was included into the chemical formulae of CaPO4. Nevertheless, this topic kept devel-
oping. For example, the correct but just strange looking chemical formula of apatite as 3 Ca3O3, P2O5 þ Ca Cl F might be found on
page 29 of a book published in 1841 [61]. However, in another book of 1841 [62] the numerical subscripts were replaced by
superscripts; therefore, the chemical formula for bone phosphate of lime was written as 8CaO þ 3P2O5, that for triphosphate of
lime as 3CaO þ P2O5, that for diphosphate of lime as 2CaO þ P2O5 þ 1 eq. basic water and one for phosphate of lime as
CaO þ P2O5 þ 2 eq. basic water (p. 304). Obviously, the term “basic water” means acidic orthophosphates; therefore, these
formulae were the first correct ones for CDHA, TCP, DCPD/DCPA and MCPM/MCPA, respectively (hydrate water was not
mentioned yet). In a book of 1843 [28], Thomson published a big table of the atomic weights of animal substances, in which he
mentioned the composition of phosphoric acid as Ph2O5 (p. 695). Rather similar ways of writing were used in some later
publications, such as one of 1854 [63], in which the chemical formula of “calcis triphosphas. – triphosphate of lime.” was written
as 3CaO,PO5 (p. 625) and the chemical formulae of other CaPO4 were written as 2CaO,PO

5
(p. 626) and 8CaO,3PO5 (p. 627),
5 Cl
that of 1855 [64] and of 1859 [55]: “Apatite has the composition 3 PO ; 3CaO Ca” (p. 128). In the latter formula, anions
F
are placed ahead of cations. In addition, in 1843 and 1845 John Percy published identical papers [65,66] (another example of
redundant publications?), in which he described formation of “a new hydrated phosphate of lime” with a chemical formula
2CaO þ PO5 þ 6HO, in which “1 equiv. water being basic and 5 constitutional.” Obviously, the “basic water” means existence of
HPO4, which is typical for DCPD, OCP, and CDHA, while the “constitutional water” is the hydrate water. Since only OCP
contains a combination of HPO4- with 5 molecules of hydrate water (Table 1); presumably, John Percy prepared OCP.
With a few exceptions [57,64–66], the aforementioned information on apatites and other CaPO4 was taken from various
books. In addition, a limited amount of journal publications of the first half of the nineteenth century is also available. Namely,
research papers on the subject were published by the famous Swedish chemist Jöns Jacob Berzelius (1779–1848) [67,68], as well
as by G.O. Rees [69], M. Baruel [70], the English physician and chemist Henry Bence Jones (1813–1873) [71–73], J.D. Smith [74],
and J.L. Lassaigne [75]. Among them, a paper of 1845 by Jones [71] should be noted. Namely, let me quote a figure caption:
“Figure 2. Amorphous deposit in alkaline urine. Deposit on boiling phosphate of soda with chloride of calcium, or with sulphate
of magnesia” (p. 349). This statement might be considered as the earliest mentioning on a precipitated ACP [76], which was made
50 years before discovering X-rays in 1895 by the famous German scientist Wilhelm Conrad Röntgen (1845–1923). Furthermore,
Jones published the earliest found pictures of precipitated crystals and some of them belonged to CaPO4 (Figure 1). Next early
pictures of CaPO4 precipitates from urine might be found in publications of 1859 [77] and 1860 [78].
In the end of 1840s, the earliest found solubility experiments of CaPO4 were performed by Lassaigne [75]. Those experiments
were made in water, saturated with carbon dioxide. The following data were obtained by 1847: “1. Pure phosphate of lime, obtained
by the double decomposition of a calcareous salt and alkaline phosphate; the solubility was 0 000 750. 2. Fresh bone, a piece of
nearly two inches long, 46/100 dths of an inch wide, and 4/100 dths thick; solubility 0 000 166. 3. Bone disinterred after about
twenty years’ repose in a cemetery, the subsoil of which was sandy; solubility 0 000 300” [75]. One can see that the solubility
value of pure phosphate of lime (presumably, it was either precipitated ACP or CDHA) was found to be higher than those of
bones. In 1849, it was written that “M. J. L. Lassaigne, at the meeting of the Academy of Sciences of Paris, of the 15th January,
presented a memoir upon this subject, showing by experiments that the phosphate and carbonate of lime are introduced into
plants in solution in water containing carbonic acid, which had before been shown as to the phosphate by M. Dumas, and has
long been known as to the carbonate” [79]. Thus, a higher solubility of both CaPO4 and calcium carbonate in very weak acids was
already known. The solubility data were updated in a publication of 1855 [80]: “Apatite dissolves in 393,000 parts of water
saturated with carbonic acid; Artificial neutral phosphate, freshly precipitated, in 1503 parts; Artificial basic phosphate, freshly
Figure 1 The earliest available pictures of precipitates, some of which contain CaPO4: “Figure 1. Iridescent pellicles on some alkaline urine.
Figure 2. Amorphous deposit in alkaline urine. Deposit on boiling phosphate of soda with chloride of calcium, or with sulphate of magnesia.
Figure 3. Chloride of calcium with acid phosphate of soda, or with common phosphate of soda ; after long standing. Figure 4. Phosphate of soda
with little chloride of calcium. Bone-earth phosphate. Figure 5. On boiling phosphate of soda with sulphate of magnesia and little biphosphate of
soda. Figure 6. Phosphate of soda with sulphate of magnesia; after long standing” (p. 349). Namely, the precipitates on Figure 2 are ACP (in the
case, calcium chloride was used) and the crystals on Figures 3 and 4 are either DCPD or OCP. Reprinted from Ref. [71].
precipitated, in 1102 parts; …” (p. 27). Furthermore, “apatite requires 356 times as much liquid for its solution, as the same salt
artificially prepared; …” (p. 28). Obviously, the “artificial basic phosphate, freshly precipitated” was ACP and, indeed, the
differences in solubility values between ACP and the stoichiometric well crystallized HA might be that big. The results of the
successive solubility experiments were published in 1866 [81], 1868 [82], 1871 [83,84], and 1883 [85].
The second half of the nineteenth century started with ‘Chemistry’ by Wilson, published in 1850 [86]. The following parts from
that book are worth quoting: “797. Phosphates of Lime. – There are many compounds of lime and phosphoric acid, owing to the
peculiarity of that acid in relation to the number of equivalents of base it combines with at once. The most interesting phosphate of
lime is that which occurs in bones, and is distinguished as the bone-earth phosphate, 3CaO,PO5” (p. 219). Thus, various types of
CaPO4 were known by that. However, the preparation technique sounds unusual to the modern readers: “The phosphorus combines
in part with the oxygen of the lime, CaO, to form phosphoric acid, and this with undecomposed lime, to form phosphate of lime,
CaO,PO5. At the same time another portion of the phosphorus combines with the calcium of the lime, forming phosphuret of
calcium, CaP” (p. 164). Thus, the compositional differences between the chemical formulae of the oxygen-containing calcium
phosphates and the oxygen-free calcium phosphides were clearly established by 1850. The earliest found thesis on CaPO4 subject was
defended in 1853 [87]. In 1856, Eben Norton Horsford, a professor in Harvard University, took out a patent for preparation of
MCPM [88], followed by another patent of 1864 [89], in which he described preparation of double orthophosphates of calcium and
sodium. Thus, one can claim, that binary salts of CaPO4 with other ions were known since, at least, 1864. In a publication of 1859,
various preparation techniques of apatites were described as follows [55]: “M. Daubrée has prepared apatite by passing chloride of
phosphorus over lime; M. Mauross and M. Briegleb, in continuation of the remarkable researchers made in the laboratory of
Professor Wöhler, have reproduced apatite in more distinct and more beautiful forms by taking advantage of the double decom-
position of alkaline phosphates and chloride of calcium; M. Forchhammer, by acting on phosphate of lime with chloride of sodium,
has obtained very beautiful specimens of the same mineral species” (pp. 129–130). Here, the readers’ attention is also paid to the
names of other early contributors to the CaPO4 subject.
In ‘Chemistry’ by Brande and Taylor, published in 1863 [90], one can find the following statements: “COMMON PHOSPHATE OF
LIME; TRIBASIC PHOSPHATE OF LIME; BONE PHOSPHATE; (3(CaO),PO5). – This salt occurs abundantly in bone-ash, and is found as a
mineral product” (p. 331). Furthermore, “Native phosphate of lime (bone phosphate) occurs in apatite, moroxite, phosphorite, and
asparagus stone; its primitive form is a six-sided prism: it also occurs in some volcanic products” (p. 332). Thus, a similarity between
the inorganic phase of bones and CaPO4 rocks of natural origin (apatite and phosphorites) was established by 1863. “When a
solution of bone-earth in hydrochloric or nitric acid is boiled to expel all carbonic acid, and decomposed by caustic ammonia, the
bone-phosphate separates in the form of a bulky precipitate, which, when perfectly dried, is white and amorphous” (p. 331). This
seems to be the second earliest mentioning on a precipitated ACP.
Further historical description is based on the journal publications only. Namely, C. Morfit [91], Robert Warington (there were
two chemists with this name, presumably, a father (1807–67) and a son (1838–1907)), who performed the earliest well docu-
mented systematic studies of the outstanding quality [81,82,92,93], and R. Fresenius [94] also worked with CaPO4. Among them,
one should notice that Morfit wrote the chemical symbol of phosphorus as Ph, thus, the chemical formula of tri-basic phosphate
was written as 3CaO, PhO5 [91].
Among the available publications written by two Robert Waringtons [81,82,92,93], Ref. [92] of 1866 by Robert Warington Jr.
deserves both a special attention and extensive quotations: “Mitscherlich tells us, that when chloride of calcium is added to
ordinary disodic phosphate, the latter being maintained in excess, the precipitate formed is tricalcic phosphate, while the solution
becomes acid from the production of monosodic phosphate. Berzelius, on the contrary, states, that the precipitate formed under
these conditions is not tricalcic phosphate, but the octocalcic triphosphate, which lie has elsewhere described. All experimenters
agree, that when the operation is reversed, and disodic phosphate is poured into an excess of chloride of calcium, the precipitate is
neither tricalcic nor octocalcic, but dicalcic phosphate” (pp. 296–297). Thus, TCP, DCP and OCP have been differentiated from
each other by 1866, while, in fact, at least, 20 years earlier because Berzelius died in 1848. Furthermore, the researchers were
already aware on the fact that the type of a precipitated CaPO4 depended on a sequence of the mixing reagents.
To prove, that OCP indeed was already known by 1866, let me make another quotation from Ref. [81]: “Octocalcic phosphate
can only be produced by the simultaneous formation of monosodic phosphate:
8CaCl2 þ 5Na4 H2 P2 O8 ¼ Ca8 H2 P6 O24 þ 16NaCl þ 2Na2 H4 P2 O8 ” ðp: 300Þ
One can see a balanced chemical equation, almost identical to the modern ones. It is hard to believe, that it was published in
1866! It is interesting to note that only 22 years appeared to be enough to perform a transition from the primitive chemical formulae
without oxygen, such as 2.Ca2P and 5.Ca2P [58], to the modern chemical equations. More to the point, the chemical formulae of
hydrated forms of CaPO4 were known by 1866 [81]: “8 73 grs. of the vacuum-dried salt, lost on ignition 12 30 grains, or 26 35 per
cent.; the formula Ca2H2P2O8 4H2O, demands 26 16 per cent. of water” (p. 299). Needless to explain, that ‘Ca2H2P2O8 4H2O’
represents two molecules of DCPD (see Table 1). Furthermore: “It is interesting to observe that while disodic phosphate is of an
alkaline nature, dicalcic phosphate possesses faint acid properties” (p. 300). In addition, the form and shape of DCPD crystals were
described as well: “The crystalline form of the dicalcic tetrahydrated phosphate has been examined by Professor Church. He describes
the crystals as thin rhomboïdal plates, of which the diagonally opposite acute angles are sometimes truncated, hexagonal forms being
thus produced. This truncation seems to be occasionally hemihedral, and then may proceed up to the diagonal between obtuse
angles; from this change triangular forms arise. Other modifications are also met with” (pp. 300–301). Another interesting con-
clusion might be found here: “We may then safely affirm that whenever dicalcic phosphate, octocalcic triphosphate, or any phos-
phate of intermediate composition, is precipitated from solution by ammonia, the salt obtained will be the octocalcic triphosphate; a
tricalcic phosphate cannot be obtained in this manner. The following is probably a type of the reaction:–
4Ca2 H2 P2 O8 þ 6NH3 ¼ Ca8 H2 P6 O24 þ 6NH4 P2 O8 ” ðpp: 301–302Þ
This seems to be the earliest mentioning on the fact that TCP cannot be precipitated from the aqueous solutions (currently we
know that ACP or CDHA are precipitated instead). In addition, the following citation from the same publication [81]: “It is quite
possible that precipitated tricalcic phosphate may possess somewhat different solubilities, when prepared by different methods; this
difference can, however, scarcely be great” (p. 304) has two important consequences: (1) by 1866, this fact was not quite clear yet; (2)
it indirectly points to variability in the Ca/P ratio for the precipitated ACP or CDHA, which results in different solubilities.
The latest available publication by Warington of 1873 [93] was devoted to the hydrolysis of a freshly precipitated TCP (i.e.,
either ACP or CDHA) to the stoichiometric HA under continuous (up to 50 h) boiling in distilled water. From the results of
numerous chemical analyses the author concluded that during boiling an aqueous suspension of the TCP was slowly transformed
to a suspension of 3Ca3P2O8.CaOH2O (i.e., HA – see Table 1) and soluble acidic CaPO4. The following conclusion was made:
“Since it appears that all phosphates of calcium less basic than apatite are unstable under the continued action of pure water, it
seems probable that a more exact examination of natural phosphates would show that many phosphates now regarded as tricalcic
are in fact of a more basic nature” (p. 989). Thus, the apatitic nature of the majority of natural CaPO4 has been predicted in 1873.
The next found journal article on the TCP hydrolysis was published in 1929 only [95].
Now it would be logical to cite a publication of 1906 by Wells [96]: “The apparent constancy of the proportion of carbonate and
phosphate of calcium in bones made an impression on Hoppe-Seyler in 1862, and we find him speculating on the possibility of the
components of the two salts being joined together to form one giant molecule: 3(Ca3(Po4)2)-CaCo3, which he imagined might be
united in some such way” (p. 522) – see Figure 2. Further, Wells mentioned: “This formula is interesting chiefly from the historical
standpoint, but it serves to emphasize the tendency of these salts to appear in nearly constant proportions in the animal body, a fact
possibly of some importance” (p. 523). Obviously, the atomic arrangement shown in Figure 2 represents the earliest structural
drawing of a single molecule of an ion-substituted CaPO4, currently known as carbonate apatite. An attentive reader will notice two
different types of calcium (currently known as Ca(1) and Ca(2)) in that structure. Besides, that time, apatites were considered as
combined compounds, which results from this citation of 1879 [97]: “Calcium phosphate, combined with calcium chloride or
calcium fluoride, occurs in the well-known minerals, apatite and osteolite” (p. 188). One might guess that, in the nineteenth century,
the atomic arrangement of single molecule of carbonate apatite (Figure 2) could have inspired researchers to compose similar
drawings for the single molecules of FA, HA, and/or chlorapatite; unfortunately, nothing on this matter was found in literature.
Although oxygen appeared in the chemical formulae of CaPO4, at least, in 1841 [61,62], even in 1856 there were publications
containing formulae without it. For example, Damour wrote phosphorus as Ph, fluorine as Fl and hydrogen as H with dots above
them, which resulted in the following formula for apatite [98]: . Here, one should also discuss the topic of
writing the chemical formula for apatites. As clearly seen from the aforementioned formulae, in the nineteenth century, apatite was
always considered as a blend of two different compounds, one of which was TCP. Therefore, researchers tried to develop a way to
8
>
< CaF2
combine these compounds into a single chemical formula of apatite. Let me show an attempt of 1883 [99]: 3Ca3 ðPO4 Þ2 þ 1 CaCl2
>
:
CaO
(p. 2464). It is important to notice, that the latter formula was proposed by an English agricultural chemist John Christopher Augustus
Voelcker (1822–84), who, in 1883, first discovered an apparent halogen deficiency in some natural apatites. Therefore, 1883 might be
Figure 2 The earliest available structure of a bone mineral, currently known as carbonate apatite. Reprinted from Ref. [96].
accepted as the earliest mentioning of OA. To honor this event, a name ‘voelckerite’ was introduced in 1912 by A.F. Rogers (1887–
1957) for a hypothetical mineral with the chemical composition of 3Ca3(PO4)2 þ CaO (i.e., pure OA) [100,101].
Chemical equations, describing various interactions between calcium phosphates and other chemicals have been known since,
at least, 1863. For example, the afore-cited production processes of both orthophosphoric acid and white phosphorus from the
Lavoisier book [36], in 1863 were written using chemical equations [90]: “When bone-phosphate is digested in dilute sulphuric
acid, it is resolved into sulphate of lime and (if a sufficiency of sulphuric acid be used) phosphoric acid: 3(CaO),PO5 þ 3SO3 ¼ 3
[CaO,SO3] þ PO5” (p. 331). One can see that hydrogen was not included into the chemical formulae yet. Nevertheless, already in
1866, it was included by Robert Warington Jr. [81] (see above). Furthermore, chemical formulae of various types of phosphates
(namely, metaphosphate and acid phosphate), as well as differences in their solubility were known by 1881 [27]: “In order to
prepare phosphorus, the bone-ash is first mixed with so much dilute sulphuric acid as to form the acid phosphate:–
Ca3 ðPO4 Þ2 þ 2H2 SO4 ¼ CaH4 ðPO4 Þ2 þ 2CaSO4
The solution of this soluble acid phosphate is next poured off from the precipitated gypsum, and evaporated to dryness, after
which, the solid residue being heated to redness, water is given off and calcium metaphosphate formed:–
CaH4 ðPO4 Þ2 ¼ CaðPO3 Þ2 þ 2H2 O
This salt is then carefully mixed with charcoal, and heated to bright redness in earthenware retorts shown in Fig. 147, when the
following change takes place:–
CaðPO3 Þ2 þ 10C ¼ P4 þ Ca3 ðPO4 Þ2 þ 10CO” ðp: 460Þ
Now, it is time to describe miscellaneous studies on the subject. The first accessible journal paper on detection and preservation
techniques of various deposits, including CaPO4, was published in 1852 [102]. Presence of CaPO4 in teakwood was established in
1862 [103]. Neutral phosphates of lime were further investigated in 1872 [104]. Various analytical topics on CaPO4 chemistry has
been studied since, at least, 1863 [105] and remained to be a subject of active research approx. until 1910s [106–119]. The
quantitative analysis of a CaPO4 sample was performed in 1884 [120], followed by remarks by C. Glaser in 1885 [121]. In 1880s,
occurrence of apatite [122] and TTCP [123–125] in metallurgical slags was discovered. The latter discovery belongs to the German
metallurgist Gustav Hilgenstock (1844–1913), after whom TTCP is called hilgenstockite. An attempt of a direct estimation of
phosphoric acid as the tribasic phosphate of lime was performed in 1888 [126]. A chemical interaction of TCP with carbon dioxide
and iron hydroxide was investigated in 1891 [127].
Besides, in the second half of the nineteenth century, CaPO4 were extensively investigated as fertilizers. As written above, the
term ‘superphosphate’ has been known since 1795 [41] and was further developed in 1803 [128]: “The phoſphoric acid ſeparated
from that portion of lime, immediately combines with the reſt of the phoſsphate of lime, and forms ſuper phoſphate of lime,
which is not farther decompoſable by ſulphuric acid” (pp. 394–395). Obviously, initially it represented just acidic CaPO4.
However, by the second half of the nineteenth century, a fertilizer with the same name became popular. It consisted of ‘a mixture
of the last-mentioned compound and sulphate of lime’ [97]. According to Pusey [129], this finding belongs to the famous German
chemist Justus Freiherr von Liebig (1803–73), who is considered as ‘the father of the fertilizer industry’ for his discoveries. Let me
cite Pusey [129]: “DR. LIEBIG’S great discovery of dissolving bones in sulphuric acid for the purpose of manure, has been so clearly
established by the experiments as well of the Duke of Richmond as of other farmers, and so fully investigated by Mr. Hannam, that
nothing seems now to be wanted but some plan for bringing it within the ordinary routine of farming” (p. 324). In 1843, an
English theologian, geologist and paleontologist Prof. William Buckland (1784–1856) wrote the following about Liebig [130]:
“Professor Liebig five or six years ago invited the attention of agriculturists to the possibility of applying to the same use as bone-
dust and guano the fossil bones and coprolites which occur together in certain beds of the lias formation” (p. 520). However, the
major breakthrough in CaPO4 usage for agriculture came from the work of John Bennet Lawes, Esq., who, in 1843, got a patent
[131] with the following claim: “The combination for the purposes of manure, of bones, or bone-ash, or bone dust, or apatite, or
phosphorite, or any other substance containing phosphoric acid, with sulphuric acid, as aforesaid” (p. 72).
In a publication of 1864 [132], one can read the following: “Now, superphosphate of lime is composed, necessarily,
of soluble phosphate of lime and plaster, or sulphate of lime formed from a combination of the sulphuric acid employed in the
manufacture of superphosphate with the lime of the bones” (p. lv). More than 20 research papers on superphosphate were
published by the beginning of the twentieth century, which indicated to the importance of this chemical for the human
being [133–155]. One can see that almost all of these studies were performed and published by single researchers (see individual
comments to Refs. [134,140]), while the majority of the investigations were devoted to analytical chemistry. Further historic
details on CaPO4 as fertilizers are available in a chapter entitled ‘An Introduction to the Industrial Phosphates Industry’
of Ref. [156].
Although vitrification properties of some forms of CaPO4 at heating have been known since, at least, 1804 [40], the earliest
accessible journal paper on this topic was published in 1877 [157]. The modern chemical formula of perfectly transparent crystals
of natural FA as Ca5(PO4)3F has been known since, at least, 1873 [158], while chemical formulae of DCP (as “Mono-Hydrogen
CaPO4, HCaPO4”) and MCP (as “Tetra-Hydrogen Calcium Phosphate, H4Ca(PO4)2”) [97] have been known since, at least, 1879
(pp. 205–206). Interestingly that in a publication of 1871, the chemical formulae of CaPO4 were written in different ways: as
3CaO PO5 for apatite and CaO 2HO PO5 for “some acid phosphate of lime” [84]. Thus, by the 1880s, the writing rules for
chemical formulae of inorganic compounds were not standardized yet.
Further, one should briefly mention on the earliest biochemical applications of CaPO4. Let me cite a couple of self-explanatory
sentences from a publication of 1935 [159]: “Calcium phosphate was used for enzyme separation as early as 1860 by Brücke (cited
by Effront, 1917). Its use for precipitation of active immunological material was advocated for the purification of diphtheria toxin
first by Roux and Yersin in 1889, …” (p. 150). Thus, the famous French physician, bacteriologist and immunologist Pierre
Paul Émile Roux (1853–1933) and the famous Swiss and French physician and bacteriologist Alexandre Emile Jean Yersin (1863–
1943) also contributed to CaPO4 by performing absorption and purification of diphtherial toxin.
Finally, one should report the investigations, performed by a British clinician and pharmacologist Sydney Ringer (1836–1910),
whose name is remembered in a Ringer’s solution. It is an aqueous isotonic solution of several inorganic salts mimicking the body
fluids of animals [160]. Within 1882–85, Ringer determined that a solution perfusing a frog’s heart must contain several inorganic
salts in a definite proportion if the heart was to be kept beating for long [161–165]. The following citation from his works is worth
mentioning [163]: “(g) So that we find we possess an excellent circulating fluid capable of maintaining the heart for several hours,
which consists of phosphate of calcium saline, with potassium chloride” (p. 19).
To conclude the 1800s, one should recognize that the majority of the fundamental discoveries in chemistry of CaPO4 were
made in the nineteenth century.
4.3 From 1900 till 1950

Since the modern scientific databases comprise scientific papers published after 1900, the history of CaPO4 in the twentieth
century is based on the journal publications only. This approach allows establishing the real chronological order. However,
the detailed description of every publication on the subject becomes impossible due to a continuous increasing amount
of them.
The twentieth century started with the systematic studies performed by F.K. Cameron with co-workers [155,166–174]
and H. Bassett [175–179], followed by publication of 1958 [180]. Namely, in 1908, Bassett composed the first version of the
solubility diagram CaO–P2O5–H2O (Figure 3) [177]. In a paper of 1917 [178], Bassett mentioned some interesting statements,
which currently look strange. Namely, there is a section entitled “The Acid from which Hydroxyapatite is Derived” (pp. 635–636),
in which he wrote the following [178]: “The usual view seems to be that in a “basic” salt, the part of the base over and
above that required to form what is considered to be the “normal” salt plays a different role in the molecule from that
played by the rest of the base. This is brought out by the method of formulation – (Ca3P2O8)3CaO – which is customary, but
which the author thinks is not good. He would suggest that oxy- (or hydroxy-) apatite, and possibly even tricalcium
phosphate, are related to mono- and di-calcium phosphate rather in the same way that an orthophosphate is related to a
pyrophosphate. Hydroxyapatite may well be a salt of an acid, H11P3O13, in which one acidic hydrogen is still unneutralised” (p.
635). Further, he speculated on an existence of other unusual types of phosphoric acid: “It is perhaps worth noting that
if the deficit in the oxyapatite analyses is all due to water, it in some cases approximates to the 3 52 per cent. required
for a compound, (Ca3P2O8),Ca(OH)2,H2O. If all the hydrogen in such a compound were acidic, the corresponding acid
would be H24P6O27 ¼ 3(H8P2O9). Now H8P2O9 is, of all the phosphoric acids, the one which has the greatest range of existence. It
is readily obtained in the crystalline condition, and can exist in stable equilibrium with phosphoric acid solutions from
about 1001 to þ 271” (p. 636). Interestingly, that the last paper of the series was published by Bassett in 1958 [180], i.e., 51
years after publication of the initial two papers of the series [175,176]. According to the literature [27,97,181], by the beginning of
1900s, researchers already operated with the individual CaPO4; however, not all the chemical formulae looked as the
modern ones. For example, Bassett wrote formulae of MCPM and MCPA as CaH4P2O8 H2O and CaH4P2O8, respectively. In
addition, he mentioned hydrated forms for TCP and TTCP as Ca3P2O8.H2O and Ca4P2O9 H2O, respectively [177], which
currently unknown.
A study on dissolution kinetics of several CaPO4 was published in 1910 [182]. Binary salts of CaPO4 with orthophosphates of
other chemical elements kept studying in 1911 [183]. In 1913, the first attempts to mimic the CaPO4 nature of bones
were performed [184]. The following formulae of carbonate apatite (left) and chlorapatite (right), respectively, were published in
1914 [185]:
Figure 3 The system CaO–P2O5–H2O in 1908. Reprinted from Ref. [177].
The osmotic properties of CaPO4 were investigated in 1915 [186]. Currently well-known chemical route of CDHA preparation
by mixing of aqueous solutions of calcium nitrate and K2HPO4 (now (NH4)2HPO4 is used instead) was investigated con-
ductometrically in 1915 [187], while a neutralization reaction of H3PO4 by Ca(OH)2 was investigated in 1923 [188]. Preparation
of CaPO4 (presumably, it was ACP) in a colloid state was reported in 1921 [189]. An interesting note on “liquid crystals of calcium
phosphate” was published in 1922 [190]; in fact, the author prepared MCPM. The earliest found paper on in vitro mineralization
using aqueous solutions containing ions of calcium and orthophosphate was published in 1926 [191], followed by publications
of 1932 [192] and 1933 [193]. Those studies might be considered as predecessors of current mineralization investigations using
simulating body fluid (SBF) and other artificial simulating solutions.
In 1917, Ramsay published important information on CaPO4 [194]: “1. The substances sold as “Phosphate of lime” and
“Calcium Phosphas B.P.” are not pure tricalcic phosphate but are mixtures of di- and tricalcic phosphates. 2. Sodium phosphate
(Na2HPO4) added to ammoniacal calcium chloride and the resulting precipitate washed with water yields a mixture of di- and
tricalcic phosphate and calcium hydrate. 3. Bone ash dissolved in hydrochloric acid and precipitated with ammonia, the pre-
cipitate being well washed, yields also a mixture of di- and tricalcium phosphate and calcium hydrate. 4. When three equivalents
of lime (3CaO) are made to act on one equivalent of phosphoric acid (P2O5) and the resulting precipitate removed with little
delay pure tricalcium phosphate is obtained.” Obviously, the obtained “mixture of di- and tricalcium phosphate and calcium
hydrate” was a CDHA; therefore, a non-stoichiometric nature of the precipitates was established by 1917. Furthermore, one can see
that chemically pure CaPO4 (B.P. means British Pharmacopoeia) were commercially produced by 1917.
Furthermore, by 1928 it was clearly known that TCP could not be prepared by wet-precipitation [195]: “We have been unable to
find any evidence of the existence of a molecular species with the formula Ca3(PO4)2. Precipitates of this “substance” rarely have the
correct empirical composition and they cannot be purified by recrystallization. The evidence is such as to lead us to suspect that
there may be no such chemical entity as Ca3(PO4)2. No one has succeeded in preparing it by precipitation (12, 35–48), bearing
out the theoretical objections to such a reaction on the grounds that fifth order reactions do not occur (49). We do not take the
position that there can be no compound with this formula. It may be found possible to synthesize it by other methods, but so far
no one has succeeded in preparing it by precipitation” (p. 128). Other researchers [196] made similar conclusions. Nevertheless,
that time this knowledge was not common yet, since, in 1935, a report was published that “Tricalcium phosphate monohydrate
was prepared by the slow addition of calcium chloride solution to a constantly agitated alkaline solution of disodium phosphate,
maintained at 651 to 70 1C” [197]. This controversy was explained in 1940 by a matter of definitions [198]: “The terms “tricalcium
phosphate” and “hydroxyapatite” are very widely and very loosely used. For example, some authors use the former for any
precipitate more basic than dicalcium phosphate, although such precipitates have been frequently shown to have an apatite lattice
or to be mixtures of dicalcium phosphate and an apatite. Others confine the use of the term to those precipitates with P2O5:CaO
ratios approaching that of Ca3(PO4)2” (p. 265). Nevertheless, papers on precipitated TCP [199,200] and even on precipitated TCP
hydrate [201] kept publishing even in 1940s. An interesting distinction between HA and precipitated TCP hydrate (obviously, it
was CDHA with x ¼ 1, see Table 1) was made in the latter paper [201]: “It seems safe to conclude that a precipitated tricalcium
phosphate can be designated as a hydroxyapatite when a 1-gram charge of 900 1C. calcine registers a dissolubility of less than 20%
by a continuously agitated 1-hour digestion in the ammonium citrate reagent at 65 1C. In contradistinction, a tertiary precipitate is
identified as a tricalcium phosphate hydrate when a like charge of its calcine shows dissolubility of as much as 50% by the
stipulated citrate digestion” (p. 169). Currently we are able to explain the solubility differences between these two calcined
samples by formation of more soluble b-TCP (Table 1).
In 1973, McConnell published a book [4], in introduction to which he wrote the following: by 1929, Hausen [202] “had
brought together considerable information, and had recognized eight different types: 1. fluorapatite, 2. alkali-containing apatite, 3.
chlorapatite, 4. carbonate apatite, 5. sulfate apatite, 6. hydroxyapatite, 7. manganapatite and 8. apatite containing rare earths” (p.
3). In addition, such terms as hydroxyfluorapatite, Ca10(F,OH)2(PO4)6, and OA were already known. Thus, ion-substituted
apatites were widely known by the end of 1920s.
The crystal structure of apatites was established in 1930 [203–205], followed by a great study on the structural characteristics of
apatite-like CaPO4 of various origin in 1931 [206]. Namely, in 1938, McConnell published the following [207]: Náray-Szabó
[208] and Mehmel [204,205] have shown that the structure of FA contains the following ions: 10Ca, 6P, 2F, and 24O. The
positions of these ions are given in Figure 4, slightly modified according Mehmel [205]. The interplanar distances for FA, from
Ontario (specimen I), with unfiltered iron radiation are given in Table 2, row 1. The calculation of the unit cell for this material is
comparable with the results of Náray-Szabó and Mehmel (Table 2) [207].
Besides, the aforementioned “hydrate of tricalcium phosphate, Ca9(H2O)2(PO4)6” with the molecular weight of 966.4 and
apatite-like diffraction pattern was mentioned as well [206]. The ‘apatite-like diffraction pattern” clearly indicates that the authors
prepared CDHA. Investigations on formation of a halogen-free HA from basic calcium phosphates were performed in 1932 [208].
The structures of carbonate apatite [209,210] and DCPD [211] were reported in 1937 and 1938. Furthermore, in 1938, several
types of CaPO4 were X-ray studied to determine their variability and phase purity [212]. The following citation from the abstract is
rather interesting: “The commercial tertiary calcium phosphates are probably hydroxylapatite with more or less adsorbed phos-
phate ions resulting in empirical formulas approaching the theoretical value for Ca3P2O8. Secondary calcium phosphate may
be admixed” (p. 156). Interestingly, that still in 1938 the structure of TCP was sometimes considered as that of HA with adsorbed
Figure 4 Projection of the unit cell of FA on (0001). The heights of the various ions are indicated as fractions of c0. Reprinted from Ref. [207].
Table 2 The comparison of the unit cell parameters for three FA samples taken from a publication of 1938 [207]
a0 c0 c/a VoI.
Fluor-apatite, Ontario I 9.3670.01 6.8870.01 0.7350 522

Fluor-apatite (Náray-Szabó) 9.3770.01 6.8870.01 0.7342 523
Fluor-apatite (Mehmel) 9.3670.02 6.8570.02 0.7317 520
PO4 ions (presumably, with the counter ions) on the surface; furthermore, the writing way of the chemical formulae was
still different from the modern one. The detailed investigations on isomorphic substitutions in apatites have been performed since
1938 [207].
In the second quarter of the twentieth century, solubility of apatites and other CaPO4 was investigated extensively. Namely,
papers on this topic were published in 1925 [213–215], 1926 [216], 1927 [217–219], 1929 [173], 1931 [220,221], 1937–1939
[222–225], 1942 [226,227], 1945 [228,229], 1948 [230–232], and 1950 [233]. In addition, in 1949, a paperback monograph (or
thesis?) on enamel-apatite solubility was published [234]. Buffering abilities of the dissolved CaPO4 have been known since, at
least, 1933 [235]. Additionally, in 1931–33, Bredig et al. [236], Trömel [237] and Schneiderhöhn (a reference was not found)
differentiated a- and b-modifications of TCP (see Table 1) and created the initial versions of the high-temperature diagram for the
binary system CaO–P2O5. In 1933, reduction experiments of TCP by carbon, carbon monoxide and hydrogen were performed at
temperatures of 900–1300 1C [238]. In addition, a new set of extensive studies on superphosphate was started in 1930s [239–247]
and continued afterwards (more recent references are not cited due to their abundance). Besides, in 1934, an important for
fertilizers reaction between urea and several CaPO4 was investigated [248]. In 1935, the heat capacity values of CaPO4 were
measured [249]. Very popular at the turn of this millennium silicon- (or silica-) contained CaPO4, in fact, appear to have been
known since, at least, 1937 [250–252], simultaneously with defluorination studies of natural phosphate rocks [252–254].
Applications of CaPO4 for removal of fluorides from water have been known since, at least, 1938 [255–257], while the earliest
research paper on using CaPO4 in chromatography was published in 1942 [258].
In 1940, a fundamental study on the equilibrium in the system CaO–P2O5–H2O was published [259]. Besides, in 1940, the
available level of knowledge on basic CaPO4 (TCP, TTCP and apatites) was summarized into a big review [198], which
might be considered as the first comprehensive review on the subject. That time, the existence of OA was uncertain. In addition, the
authors of that review wrote about HA that “Existence as a unique stoichiometric compound doubtful” (p. 259, Table),
which was a clear indication to the great difficulties to synthesize HA but not CDHA. Furthermore, the following
important assumption was made: “First, between dicalcium phosphate and lime, there exists, in the ternary system, a continuous
series of solid solutions having an apatite lattice. It follows from this that tricalcium phosphate and hydroxyapatite do not exist in
aqueous systems as unique, stoichiometric compounds” (p. 265). Thus, in 1940, existence of CDHA with variable Ca/P
ratio was predicted. The idea on a continuous series of solid solutions was further developed by 1950 [260]: “On structural
grounds it appears possible that a continuous series of apatite-like solid solutions can exist between octocalcium phosphate and
hydroxy- (or fluor-) apatite. In practice, no two preparations with composition lying between octocalcium phosphate and
hydroxyapatite are likely to be identical” (Abstract). Thus, in 1950, the distinct Ca/P borders for CDHA were established
between those in OCP (Ca/P ¼ 1.33) and HA (Ca/P ¼ 1.67). In addition, it was noted that CaPO4 precipitates with Ca/P ratios
within 1.0–1.33 “consist of at least two phases; dicalcium phosphate and a solid at least as basic as octocalcium phosphate”
(Abstract) [260].
The term ‘whitlockite’ (named after an American mineralogist Herbert Percy Whitlock (1868–1948), who was the curator of the
American Museum of Natural History, New York, USA) for ion-substituted TCP first appeared in 1941 [261]. Besides, in the same
year, a study on virus purification by adsorption on CaPO4 was published [262], followed by two other studies in 1945 [263,264].
An important study on the thermal decomposition of MCPM was published in 1947 [265], while that on high-temperature heat
content of HA appeared in 1950 [266].
To finalize the first half of the twentieth century, one should mention on an interesting conclusion, made in 1944. Namely,
attempting to explain anomalous pH drop during titration of H3PO4 by Ca(OH)2 discovered by earlier researchers
[188], Greenwald published a paper on a possibility to precipitate CaPO4 having Ca/P ratio Z2 [267]: “We may now picture the
course of events as follows: after the first equivalent of calcium hydroxide has been added, the solution contains Ca þ þ , H2PO4
and HPO4 ¼ ions. It also contains some undissociated CaHPO4.6 This may act as an acid and upon addition of Ca(OH)2
give a precipitate of Ca(OH) CaPO4, possibly occluding or adsorbing a little Ca(OH)2 as well” (p. 1306). In fact,
precipitation of Ca(OH)CaPO4 remained unproven because there is no reason, why undissociated CaHPO4 should behave as a
stronger acid if compared with H2PO4 ions. Currently, we can explain that anomalous pH drop by formation of
ACP, the chemical composition of which may vary in wide ranges (Table 1). A similar unproven conclusion on a possibility to
precipitate CaPO4 having Ca/P ratio exceeding that in HA due to adsorption of hydroxyl or other anions was published in 1950
[260].
More recent (after 1950) publications on CaPO4 are not considered, since they are well known.
5 Early Publications on CaPO4 of the Geological Origin
As written above, apatite was recognized as a calcium phosphate by 1788 [32–34]. As early as 1794, Kirwan [268] wrote a section
“Phoſphorite. Apatite of Werner” (pp. 129–130), in which one can read the following (again, pay attention to the old-fashioned using
a letter ‘ſ’ instead of ‘s’): “In Spain, it is found in extenſive ſtrata forming intire mountains; … Sometimes alſo cryſtallized in Germany,
and of greeniſh colour. In Saxony, it is found in low hexahædral priſms with truncated edges and angles, the planes of the ſides
longitudinally ſeamed, or in hexangular tables heaped one on the other,” According to Fourcroy [40]: “Citizen Vauquelin has proved,
in Frimaire, in the year 6 (November, 1797,) that the chryſolite of the jewellers is alſo calcareous phoſphate” (p. 337). Thus, CaPO4
of the geological origin were differentiated by the end of the eighteenth century. Furthermore, their complex quantitative chemical
composition has been known since the same time. To demonstrate this, let me quote an encyclopedia of 1798 [269]: “According to
the analyſis made by theſe chemiſts, 100 grains of the calcareous phoſphat is reſolvable into the following elements:
Carbonic acid 1 grain.

Muriatic acid ½
Iron 1
Quartzous earth 2
Pure calcareous earth 59
Phoſphoric acid 34
Fluoric acid 2½
——
100 Grains” (p. 624)
In 1800, Chaptal [270] wrote: “Phoſphate of Lime, Calcareous Phoſphoric Salt. This phoſphate of lime has been found in Spain,
in the kingdom of Eſtramadura, by Mr. Bowle” (p. 49). In 1804, Fourcroy [40] continued: “The phoſphate of lime never exiſts in a
regular form but among minerals. Citizen Haüy has diſcovered that its primitive form is a regular hexahedral priſm, and that of its
integrant particle an equilateral triangular priſm. He deſcribes four varieties, namely,
A. Primitive calcareous phoſphate. The Apatite of Werner.
B. Pyramidal calcareous phoſphate; formerly chryſolite; two right hexahedral pyramids, ſeparated by a priſm. This cryſtal, which
was arranged among the gems, was named chryſolite by the jewellers, on account of its golden yellow colour, and the uſes to
which it was applied in jewellery. Citizen Vauquelin aſcertained that this pretended gem is a true native phoſphate of lime ; and
Citizen Haüy has found an eſſential agreement between the form of the chryſolite and that of the Apatite of Werner.
C. Peridodecahedral calcareous phoſphate. Priſm of twelve ſides, alternately broad and narrow. Variety of the Apatite.
D. Annular calcareous phoſphate. Hexahedral priſm, having on each ſide ſix facets, diſpoſed like a ring round its baſe. Another
variety of the Apatite.
Two other known cryſtallized varieties may be added.
E. Amorphous calcareous phoſphate. It is the phoſphate of Eſtramadura ; which is opaque, lamellar, and of a ſparry
appearance.
F. Pulverulent calcareous phoſphate. Phoſphoric earth of Marmaroſch in Hungary, which Pelletier has aſcertained by analyſis to
be a mixture of the phoſphate of lime and fluate of lime” (pp. 338–339). This seems to be one of the earliest classifications of
CaPO4 of the geological origin, as well as the earliest mentioning on ACP.
In 1805, Nisbet [43] added: “Phosphated Lime, apatite or phosphorite, has been found in an amorphous state in Hungary, and
forming entire mountains in Spain. It is also found in truncated hexahedral, longitudinally striated prisms, laminated in their
transverse fracture, and generally with tin and fluor. Klaproth found it to contain acid 45, lime 55” (p. 195). In 1809, Murray [271]
wrote on natural phosphorite: “Its colour is yellowish or greyish white, without lustre or transparency; rough to the touch; and having
a specific gravity of 2.8. This substance was analysed by Pellerier, who found it to consist of lime 59, phosphoric acid 34, fluoric acid
2.5, silex 2, iron 1, with a trace of carbonic and muriatic acids” (p. 477). One can see that the reported quantitative values are similar
to the aforementioned ones of 1798 [269]. In 1811, the early pictures of natural phosphorite (Figure 5, left, in color) and apatite
(Figure 5, right) were published [272]. In 1820, R. Jameson in his fundamental book: “A System of Mineralogy” [273] published a
section entitled “Genus II. APATITE” (pp. 574–587), in which the major information on physical, chemical, crystallographic
properties of natural apatites, and phosphorites, as well as the geographic locations of major deposits were summarized. In 1822, D.
Lowry published a catechism book “Conversations on Mineralogy” [274], from which a self-explanatory discussion is worth citing:
“The family of phosphates of lime contains but two species, apatite and phosphorite.
Frances. Are they very different from each other?

Mrs. L. In appearance they are, but not in composition;
apatite is generally crystallized, and strongly translucent, or transparent: but phosphorite is always amorphous and opake”
(p. 187). Thus, the key similarities and differences between two major types of CaPO4 of geological origin were established by
Figure 5 Early pictures of natural ‘CALX phosphata’: a color picture of ‘compact phosphate of lime or phosphorite’ (left) and a picture of
‘phosphate of lime, moroxite’ (right). Reprinted from Ref. [272].
1822. The crystallographic studies of natural apatites were performed simultaneously. For example, in a publication of 1824 one
can read the following [275]: “The forms of apatite belong to the rhombohedral system of Professor Mohs” (p. 143). In addition,
the major crystallographic planes have been described in the same publication. A short abstract (just two paragraphs) on the
presence of chlorides and fluorides in natural apatites of different origin was published in 1827 [276]. Further, in 1829, the earliest
recognition of CaPO4 nature of coprolites, as fossilized feces of prehistoric animals, was published by Buckland [277]: “In all these
various formations our Coprolites form records of warfare, waged by successive generations of inhabitants of our planet on one
another: the imperishable phosphate of lime, derived from their digested skeletons, has become embalmed in the substance and
foundations of the everlasting hills” (p. 235).
In a book of 1839 [278], one can read the following: “Phosphate of lime is found in both kingdoms of nature. (a.)
In the inorganized kingdom. – It is a constituent of the mineral termed Apatite, and of some mineral waters ; as those of
Karlsbad Sprudel, and of Franzensbrunn, near Eager. (b.) In the organized kingdom. – It has been found in some plants, and much
more frequently and copiously in animals” (p. 359). The latter statement was specified in 1841 [279]: “When we consider
that the bones of all graminivorous animals contain nearly 50 per cent. of phosphate of lime, we might be at liberty to infer the
existence of this principle, in food and, consequently, in the soil, on which these animals graze. If we look at the actual result
of the analysis of beets, carrots, beans, peas, potatoes, asparagus, and cabbage, we find phosphate of lime, magnesia, and potash,
varying from 0.04 to 1.00 per cent. of the vegetable” (p. 45). Thus, all major locations of CaPO4 in Nature were established
by 1841.
In addition, in 1841, the following information on apatite was published for scholars [280]: “1. Apatite, or phosphate
of lime, is found of various colours, white, red, green, and wine yellow ; it is found massive and crystalized, associated with
other ions. 2. The crystals of apatite are smooth, low, six-sized prisms, sometimes passing into six-sized table ; they are translucent,
but seldom transparent. 3. Apatite is composed of 53.75 parts of lime, and 46.25 phosphoric acid ; its specific gravity 3.1” (p. 223).
An agricultural importance of CaPO4 became known by the same time, which results from a publication of 1845 [281],
as well as from a big paper of 1851 [282], while in 1870, the earliest found book devoted to natural phosphates was
published [283]. As seen in an advertisement from this book, “Bone Phosphate, Soluble Ammoniated” currently known as
ammoniated superphosphate was commercially produced by 1870 (Figure 6). In the latter half of the nineteenth century,
geologists discovered phosphate rock deposits in USA (1867, South Carolina [283] and 1888, Florida [284]), as well as in Russia
[285].
Regarding journal publications on the subject, the earliest paper on CaPO4 of a geological origin I have managed to find was
published in 1845 [286], followed by ones of 1848 [287], 1849 [288], 1850 [289], 1855 [290], 1856 [98,291], 1865 [292–297],
1866 [298], 1869 [299], 1871 [300], 1873 [158,301], 1875 [302], 1882, [303], 1883 [304], 1886 [305,306] and 1889 [307].
Among them, one should quote the final sentence from a paper by Moore [296]: “It is with great pleasure that I dedicate this
species to Prof. G.J. Brush, of Yale College, to whose unwearied zeal and efficient labors American Mineralogy stands so deeply
indebted” (p. 44), after which DCPD of natural origin has been calling brushite.
Furthermore, in 1882, Shepard wrote the following [303]: “This would require the formula 2CaO, H2O, P2O5 (or CaHPO4), as
a comparison of the calculated and obtained results will show. Monetite is a crystalline dicalcic hydric phosphate, or dicalcic-
ortho-phosphate, differing from that artificially prepared (by the action of calcic chloride on disodic-hydric-phosphate), in not
possessing water of crystallization as does the latter – (PO4H)2Ca2 þ 2H2O” (p. 402). Here we see a strange combination of the
Figure 6 One of a number of advertisements on CaPO4 fertilizers, 1870. Reprinted from Ref. [283].
modern-looking formula for DCPA and the old-fashioned one for DCPD. In addition, the publication of 1889 by Shaler [307]
might be considered as the earliest found journal review on CaPO4, in which the author described various types of natural
phosphate deposits, their formation, as well as possible utilization, mainly as fertilizers. Next available papers on natural CaPO4
were published in 1890 [308], 1892 [309], 1895 [310], 1901 [311,312], 1902 [313–315], and 1904 [316]. Among them, one
should mention on the earliest paper on dahllite [308], which was named in 1888 by Brögger and Bäckström after the Swedish
mineralogist brothers Tellef and Johan Martin Dahll.
An important study on the presence of orthophosphates of various chemical elements, including calcium, in soil was published
in 1906 [317], a study on nitrite bacteria which made soluble CaPO4 from the insoluble ones was published in 1916 [318],
while the presence of CaPO4 in meteorites has been known since, at least, 1917 [319]. To finalize the geological topic, let me
quote a paper by Bassett of 1917 [178]: “Several papers have been published claiming the existence of minerals (“dahllite,”
“podolite,” etc.) of the calcium apatite group with the halogen partly or entirely replaced by carbonic acid (Brögger and Bäckström,
Zeitsch. Kryst. Min., 1890, 17, 426; from Ofv. Vet. Akad. förh., 1888, 493; Schwantke, Centr. Min., 1905, 641; Tschirwinsky, ibid.,
1907, 279; Schaller, Amer. J. Sci., 1910, [iv], 30, 309; Rogers, ibid., 1912, [iv], 33, 475). Whilst the evidence brought forward in
these papers is perhaps not quite as satisfactory as could be wished, it does seem to indicate the possible existence of such
carbonate-apatites” (p. 637).
Further historical details on CaPO4 of the geological origin are available in a topical review [320].
6 Studies on CaPO4 in Living Organisms
6.1 Investigations Performed in the Eighteenth Century

As mentioned above, the first journal publications on the structure and composition of bones, teeth and other types of calcified
tissues appeared in the last quarter of the seventeenth century [19–25], while the presence of CaPO4 in bones was established in
1770s [27,30,31]. Namely, in 1788, a special chapter entitled “Concerning the bones of animals” (pp. 400–406) was published as a
part of the Fourcroy’s book [321]. Several records from that chapter are worth citing (again, pay attention to the old-fashioned using a
letter ‘ſ’ instead of ‘s’): “Theſe hard ſubſtances cannot be conſidered as paſſive in the animal economy, they are true ſecretory organs,
which ſeparate from the blood and other humours a peculiar ſaline ſubſtance, of which they are the reſervoir, or place of depoſition”
(p. 400). This is the correct description of the role of bones in general metabolism. “The bones of men and of quadrupeds, which
alone have been hitherto examined by chemiſts, are not earthy matters, as was formerly ſuppoſed: they contain a certain quantity of
gelatinous matter, diſperſed in ſmall cavities, formed by the interval between the ſolid parts which compoſу their texture; and the
ſolid parts themſelves, though they ſeem to reſemble earthy ſubſtances by their inſolubility and firmneſs, have been for ſeveral years
paſt acknowledged to be a true neutral ſalt, conſiſting of phoſphoric acid and lime” (p. 401). Thus, the bioorganic/inorganic
composite nature of bones has been known since, at least, 1788. In one of this later books [26], Fourcroy mentioned the scientists,
who contributed to this discovery: “Papin, Heriſſant, Laſſone, Haller, had carefully diſtinguiſhed and proved by experiments that the
bones were formed of two different ſubſtances; the one glutinous, ſuſceptible of diſſolving in boiling water, and forming a jelly which
was prepared for the uſes of ſeveral of the arts ; and another ſubſtance which had been conſidered as calcareous or abſorbent; …”
(p. 382). In a book of 1843 [28], Thomson added the following: “The first person that attempted an analysis of bone was Merat-
Guillot, an apothecary at Auxerre, who, about the year 1798, published a comparative analysis of the bones of man, and of a variety
of other animals ;‡ but his results were far from near approximations to the truth” (p. 235).
Concerning the level of knowledge on the presence of CaPO4 in teeth and other calcified tissues of animals, available
by the end of the eighteenth century, let me quote three self-explanatory sentences from a publication of 1797 by the American
physician, naturalist and politician Samuel Latham Mitchill (1764–1831) [322]: “More recently, Berniard (Journal de Physique,
Octobre, 1781,) obtained phosphoric acid not only from fossil bones, from those of the whale and sea-horse, but from
the tooth of the manati and the grinder of the elephant. It has also been extracted from ivory. In short, they who have experi-
mentally attended to this subject have agreed, that animal bones are chiefly composed of phosphoric acid and calcareous
earth, or are the phosphate of lime: and that their teeth consist in the main, of the like materials.” (p. 62). In addition, the
important data on the structure, composition and the presence of CaPO4 in bones and teeth were also obtained by Home [323]
and Hatchett [324].
Although, the presence of phosphorus in urine was established in 1669 by Brand, the knowledge on dissolved calcium in urine
has been available since 1780s [321]: “We have ſeen that urine contains many peculiar ſalts; theſe ſalts are combinations of the
phoſphoric acid with volatile alkali, ſoda, and lime, and the baſe of the calculus of the bladder” (p. 353). According to a
publication of 1798 written by a British physician and chemist George Pearson (1751–1828), who published one of the earliest
journal papers on the presence of CaPO4 in urinary concretions, the discovery of CaPO4 in urine is related to the great chemists
Scheele and Lavoisier [325]: “The immortal, and ever to be deplored, Lavoisier supposed these substances to consist of acidulous
phosphate of lime and animal matter, many of them being partially fusible; but still it was the unrivalled Scheele who discovered
that the urine of healthy persons contains superphosphate, or acidulous phosphate, of lime; and who also indicated the
experiment which verified his opinion, that phosphate of lime is the basis of bone” (p. 17).
Regarding undesirable in vivo formed calcifications, the earliest journal papers on this subject were published in 1672 [326] and
1677 [327]. However, even 120 years afterwards (1791) the presence of CaPO4 in such deposits was not commonly recognized yet
[328], in spite of the fact that [325]: “Dr. Link, in a very elaborate dissertation, published at Gottingen, in 1788, on urine and calculi,
concludes that urinary concretions consist of phosphoric acid, lime, ammoniac, oil, the bases of different kinds of gazes, together
with the acid sublimate of Scheele, although he did not succeed in obtaining it” (p. 18). The famous English chemist and physicist
William Hyde Wollaston (1766–1828), after whom a calcium silicate mineral wollastonite was named, also discovered the presence
of ‘phosphorated lime’ in human calculi [329]. Furthermore, in the same paper, Wollaston wrote: “On the contrary, ossifications
(properly so called) of arteries and of the valves of the heart, are similar to earth of bones, in containing the redundant calcareous
earth; and I believe also those of veins, of the bronchiæ, and of the tendinous portion of the diaphragm, have the same excess ; but
my experiments on these were made too long since for me to speak with certainty. To these I may also add the incrustation
frequently formed upon the teeth, which, in the only two specimens that I have examined, proved to be a similar compound, with a
very small excess of lime” (p. 398). Thus, the presence of CaPO4 in arteriosclerotic deposits and other unwanted calcifications inside
the human body, as well as in dental plaques has been known since, at least, 1797.
6.2 Investigations Performed in the Nineteenth Century

Further investigations on CaPO4 in living organisms were performed in the nineteenth century. For example, the chemical
composition of teeth was established by Fourcroy and Vauquelin by 1801 [330]: “Hence, 100 parts of enamel of teeth were found
to contain :
1. Lime, 43,3.
2. Phosphoric acid, 29,67.
3. Gelatin and water, 27,10” (p. 534).
Although the reported numeric values for both bioorganic constituents (gelatin) and water in tooth enamel appear to be too
high (presumably, the authors mixed dentin and enamel), their presence in enamel was discovered by 1801. Already in 1802,
Josse, a citizen of Rennes (France), carefully studied the composition of teeth and described dental enamel as white, very fragile
and of extreme hardness, while the underlying dentin he regarded as essentially bone. In addition, he performed chemical
analyses, which revealed the presence of just calcium and phosphate in the enamel samples [331]. Further, in 1803, Count Carlo
Morozzo of Italy published a study of fossil tooth [332], followed by a publication of 1805 by an Italian chemist Domenico
Morichini [333]. The presence of fluorides in bones and teeth was found by 1805 [334,335].
By 1808, the aforementioned data were further updated. Let me cite the section “teeth” from a dictionary of 1808 [336]: “A
letter from Mr. Gehlen, however, to the editor of the Journal de Physique, says, the very extensive and accurate experiments of Mr.
Berzelius of Stockholm have proved, that the enamel and the bony part of the teeth of man and of the ox, as well as their bones
themselves, contain fluoric acid. The following are the results of the analyses:
Enamel of Human Teeth.

Phosphat of lime 85 3
Fluat of lime 32
Carbonat of lime 80
Phosphat of magnesia 15
Soda, combustible animal matter, and water 2
—————
100.
Enamel of the Teeth of the Ox.
Phosphat of lime 81
Fluat of lime 4
Carbonat of lime 71
Phosphat of magnesia 3
Natron 1 34
Animal matter 3 56
—————
100.
Osseous Part of the Human Teeth.
Fluat of lime 2 10
Carbonat of lime 5 50
Phosphat of magnesia 1 05
Soda, with a little muriat of soda 1 40
Gelatine, veins, and water 28 00
—————
100.
Osseous Part of the Teeth of the Ox.

Fluat of lime 3 69
Soda, with a little muriat of soda 2 40
Gelatine, veins, and water 31 00
—————
100.
Dry fresh Human Bones.
Gelatine, 32 17
Veins belonging to their organization 1 13
Fluat of lime 2 00
Soda, with a small quantity of muriat 1 20
—————
100.
Dry fresh Ox-bones.
Gelatine, Veins belonging to their organization 33 30
Fluat of lime 2 90
Soda, with a small quantity of muriat 2 45
—————
100.”
This seems to be the earliest scientific data on the substantial compositional differences among enamel, dentin and bones.
Furthermore, the fact on a negligible presence of bioorganic substances in dental enamel was already known in 1808. In addition,
the presence of carbonates, fluorides, chlorides, magnesium and sodium in the mineral phase of bones was established by that.
Finally yet importantly, this citation provides additional evidences of the great Berzelius’s contribution to the CaPO4 subject.
In 1809, the structure, composition, properties and formation mechanisms of bones were described in details in the London
medical dictionary [337]: “Bones consist of fibers crossing each other in different directions” (p. 263), “The substance of bones is now
known to be a calcareous phosphat, which is deposited by exhalent arteries; and this substance is constantly renovated, while an equal
portion is carried off by absorption” (p. 263), “Bones, we have said, owe their solidity to phosphorated lime. The bones of an adult
contain the greatest proportion of earth; those of a fœtus, of gelatin. Fish bones, from Mr. Accum’s experiments contain one-sixth part
more of phosphoric acid than the bones of quadrupeds. Carbonated alkalis decompose the phosphat of lime in bones. They contain
also a small proportion of selenite, carbonate of lime, and, according to Proust, of mineral alkali” (p. 264). Additional descriptions of
the chemical composition of various types of calcified tissues were published shortly afterwards [338,339].
Simultaneously, an importance of CaPO4 for bone growth in organisms of young mammals was established. The following self-
explanatory quotation from a book of 1812 [340] is worth mentioning: “It is remarkable, that though phosphate of lime is always
found in the urine of adults, this salt is not evacuated by infants. The rapid formation of the bones, in the first periods of life, requires
that there should be no waste of any of the phosphoric salts; and Nature, ever provident, has provided accordingly” (p. 225). In 1841,
this subject was investigated in further details by the French bacteriologist and doctor Alfred François Donné (1801–78), who
discovered that urine of pregnant women contained much lesser amounts of phosphate and sulphate of lime than that of other
women [341]: “This circumstance modifies in a very remarkable manner the microscopic crystals of the salts contained in urine, and
enables us to determine with great probability, if not absolute certainly, the existence of pregnancy” (p. 232). Thus, one of the earliest
pregnancy determination techniques was based on the concentration of the dissolved CaPO4 in urine.
Furthermore, as seen from a catechism book by Sir Humphry Davy [342], the general principles of bone and teeth formation
(biomineralization) were established by 1814: “During the earliest period of animal life they consist almost entirely of a gelatinous
membrane of the form of the bones, but of a loose spongy texture, the cells or cavities of which are destined to be filled with
phosphat of lime; it is the gradual acquisition of this salt which gives to the bones their subsequent hardness and durability. Infants
first receive it from their mother’s milk, and afterwards derive it from all animal and from most vegetable food, especially
farinaceous substances, such as wheat flour, which contain it in sensible quantities. A portion of the phosphat after the bones of the
infant have been sufficiently expanded and solidified, is deposited in the teeth, which consist at first of only a gelatinous membrane
or case, fitted for the reception of this salt; and which, after acquiring hardness within the gum, gradually protrude from it” (p. 302).
What is more, such disease as rickets (rachitis) was already known to be caused by deficiency of CaPO4: “Pray, Mrs. B. does not the
disease of the bones of children, called the rickets, proceed from a deficiency of phosphat of lime?” and response: “… The other
cause of this disorder is an imperfect digestion and assimilation of the food, attended with an excess of acid, which counteracts the
formation of phosphat of lime” (p. 303). In addition, let me cite another publication of 1815 [343]: “It is well known that there is a
disease called by nosologists malacosteon, or mollities ossium, where the bones become entirely soft. The calcareous phosphate is
almost entirely carried away, there scarcely remains any thing but the cellular tissues of the bones, with the gelatinous and greasy
part, or the marrow” (p. 491). Thus, according to the aforementioned, one can conclude, that the correct basic knowledge on the
structure, chemical composition, properties and formation processes of bones was obtained by 1820 [344].
Nevertheless, in spite of the aforementioned achievements, basic research on bone structure and composition kept going. For
example, an important study on the proportions of the inorganic and bioorganic compounds in different bones of
human body was published in 1838 [345]. The author demonstrated that different bones contained different compositional
relationships between the inorganic and bioorganic compounds; moreover, similar differences between the bone compositions
of fetal and adult organisms were also detected [345]: “The existence of a general law, regulating the proportion of earthy deposit
in the different bones, (which is shown by the curious agreement of relative proportion observed between the fœtal and adult
skeletons,) adds one more to the many proofs of the regularity and perfectness of design which Nature evinces in her operations”
(p. 413). In addition, an informative paper on bones and their applications in the arts was published in 1838 [346]. In 1843, the
presence of fluorides in bones was further investigated [347] and, in 1844, an important book on the chemical composition of
bones and teeth was published [348]. Let me quote a publication of 1850 [349]: “The composition of the phosphate of lime
contained in bones, has generally been assumed upon the authority of Berzelius to be represented by the formula 8 CaO, 3 PO5.
Some chemists, however, e. g. Marchand and Boussingault, have expressed an opinion that the true composition of this compound
should be expressed by the formula 3 CaO, PO5” (pp. 364–365). In is important to notice, that both discussed values of the Ca/P
ratio in bones are below that that in the stoichiometric HA; thus, Ca-deficiency in bone apatites has been known since, at least,
1840s. Significant information on the state of some minor chemical elements in bones became known by 1850s [63]: “Bone
ash consists principally of triphosphate of lime, but mixed with carbonate and a small portion of sulphate of lime. The sulphate did not
pre-exist in the bones, but is formed during calcification by the oxidation of the sulphur contained in the animal matter of the
bone [350]. Thomson [351] mentions magnesia (not in the state of phosphate) and chloride of sodium as constituents of bone earth”
(p. 626). However, the earliest accessible journal publication, devoted to the importance of CaPO4 to bone health was published
in 1842 [28], followed by a study of 1895 [352], while further journal papers on CaPO4 of bones were published by Aeby within
1872–1875 [353–357], as well as by other researchers [358,359]. Aeby established the composition of a bone mineral as
[6Ca3P2O8 þ 2H2O þ 2CaO þ CO2] þ 3H2O with distinguishing two types of water [356,357].
In the second half of the nineteenth century, the compositional differences between bones belonged to young and old
individuals were extensively investigated. Let me cite a summary on this topic, published in 1928 [360]: “In 1855 Frémy (4)
concluded that in humans there is, with increasing age, a relative increase of CaCO3 with respect to calcium phosphate [64]. Von
Recklinghausen (5) in 1858 concluded from his own analyses and from the work of Bibra (1844), of Stark (1845), of Heintz
(1849), and of Frémy, that there was no observable difference in composition between the bones of young and those of old
individuals. In 1860 Milne Edwards (6) reported that his own analyses agreed with those of Bibra and of Frémy in showing that
the proportion of carbonate in the bones of young animals was smaller than in adult bone. Zalesky (7) in 1866 reviewed the
literature and concluded that the bones of children of various ages have the same composition as those of adults, not only as a
whole, but also as regards the proportion of individual constituents. He pointed out that the methods of determining CO2
employed by previous investigators were defective. In 1872 Wildt (8) analyzed the ashed bones of rabbits of different ages and
found an increase in the proportion of CO2 with increasing age. Weiske (10) in 1889 analyzed the ashed bones of birds and found
an increase in CaO and CO2 with advancing age, while the P2O5 remained constant. Graffenberger (11) in 1891 analyzed
the ashed bones of rabbits and also found an increase of the ratio calcium carbonate : calcium phosphate with increasing age”
(pp. 155–156). Similarly, in 1917, Bassett wrote the following [178]: “Several papers deal with the question of bone carbonate.
Gabriel (loc. cit.), Aeby (J. pr. Chem., 1872, [ii], 5, 308, also Ber., 1874, 7, 555), and Gassmann (Zeitsch. physiol. Chem., 1910, 70,
161) have suggested that the carbonate present in bone is combined with the phosphate, but so far no very satisfactory conclusions
have been reached on this point” (p. 637). These citations clearly demonstrate that the chemical composition of the inorganic
phases of bones was a hot topic of research that resulted in updating the data on bone composition (Table 3) and Ref. [361].
Knowledge development on the constitution of the tooth enamel was performed as well [362].
To change the subject, let me inform that the importance of CaPO4 to formation of cells in various organisms was established
by 1851 [363,364]. To demonstrate this, let me quote a couple of sentences [363]: “2ndly. – The want of phosphate of lime, either
in plants or animals or men, causes a deficient formation of cells; and a great many pathological states of the system really seem to
depend upon a deficiency of phosphate of lime. … 4thly. – I have shown by my experiments, that such really is the effect of the
administration of phosphate of lime; that is to say, I have produced, by the internal administration of phosphate of lime, an
undoubted increase of the cell-formation in diseases evidently showing a diminished formation of cells” (p. 431). Additional
citations from both papers are given in Section 7 of this manuscript.
Regarding the presence of CaPO4 in other parts, organs and fluids of the human body, according to the Fourcroy’s book [40],
the presence of CaPO4 in major biological fluids was established by 1804: “Citizens Berthollet and Fourcroy confimed the
diſcovery of Scheele reſpecting the preſence of phoſphate of lime in human urine. They found it alſo in milk, in blood, in the
muſcles, in jelly, &c” (p. 537). These data were extended afterwards. Namely, let me quote a section devoted to milk, published in
Table 3 The chemical composition of two bone samples taken from a publication of 1871 [83]
Commercial bone-ash Pure ox bone-ash
Moisture and volatile matter 6.70 1.86

Siliceous matter 9.69 0.51
Oxide of iron 0.58 0.17
Lime 43.37 52.46
Magnesia 1.14 1.02
Phosphoric acid 33.68 39.55
Carbonic acid, alkalies, and other substances undetermined 4.84 4.43
Total 100.00 100.00
1815 [365]: “5. Milk. – In 1813 C. F. Schwarz published an inaugural dissertation at Kiel on the analysis of milk. From 1000 parts
of cow’s milk he obtained the following substances :–
Phosphate of lime 1 805

Phosphate of magnesia 0 170
Phosphate of iron 0 032
Phosphate of soda 0 225
Muriate of potash 1 350
Lactate of soda 0 115
__________
3 697
1000 parts of human milk contain,
Phosphate of magnesia 0 500
Phosphate of iron 0 007
Phosphate of soda 0 400
Muriate of potash 0 700
Lactate of soda 0 300
__________
4 407” (pp. 41–42)
And the following information on the chemical composition of urinary calculi was published in the same book [365]: “4.
Urinary Calculus of A Horse. – A urinary calculus of a horse analysed by Professor Wurzer was found to contain the following
constituents :–
Carbonate of lime 66
Carbonate of 4 06
magnesia
Red oxide of iron 0 005
Animal matter 9 885
__________
100 000” (p. 41).
Furthermore, according to the Universal Technological Dictionary, published in 1823 [366], by that time, the presence of
phosphate of lime was also found in bile, tears, mucus, cerumen, synovia, semen, urinary calculi, hair, nails, as well as in ivory,
and hartshorn (article ‘Chemistry’), while CaPO4 in saliva were discovered by 1842 [367,368]. In addition, by 1827, CaPO4 were
discovered in excrements [369]: “Thacr and Einhof obtained, by ignition, from 3840 grains of the excrements of cattle, fed at the
stall chiefly on turnips, the following earths and salts :–
Lime, 12
Phosphate of lime, 12 5
Magnesia, 20
Iron 50
Alumina with some manganese, 14 0
Silica, 52 0
Muriate and sulphate of potash, 12
____
98 7” (p. 458)
The presence and properties of CaPO4 in urine were investigated in further details by Bird [370], Liebig [371], Roberts [372],
Jones [71–73,373], Hassall [77,102,374] and Smith [375], while the presence of CaPO4 in the auditory system of mammals has
been known since, at least, 1879 [376]. The earliest accessible journal paper on a behavior of an undisclosed CaPO4 in organisms
of carnivores was published in 1883 [377], while a detailed study on the chemical composition of dental enamel was published in
1896 [378].
Concerning the undesirable calcifications, the presence of CaPO4 in such deposits was confirmed in 1802 [379]: “The result of
all these experiments is, that these pulmonary stones or concretions are true PHOSPHATES OF LIME” (p. 260), as well as in 1808 [380], 1819
[381] and 1821 [382]. Interestingly that the famous English scientist Michael Faraday (1791–1867), whose main discoveries
included those of electromagnetic induction, diamagnetism and electrolysis, also participated in studies on unwanted calcifica-
tions. To demonstrate this, let me quotee a publication of 1829 [383]: “I am happy in having had the kind assistance of Dr. Prout,
and of Mr. Faraday of the Royal Institution, in ascertaining the existence of carbonate of lime, in some of the specimens of calculi
in which that substance is not usually looked for” (p. 79). However, to the best of my findings, the journal publications on the
in vivo formed CaPO4-containing undesirable calcifications were in print only in the second half of the nineteenth century: in 1856
[384], 1882 [385], and 1883 [386]. In addition, it is important to mention a book [387] written by a famous German doctor,
anthropologist, pathologist, prehistorian, biologist, and politician Rudolf Ludwig Karl Virchow (1821–1902), in which he
introduced a term ‘metastatic calcification.’
To finalize the nineteenth century, it is worth mentioning that the presence of CaPO4 in corals in amounts of B0.25% was
found in 1846 [388], while the first accessible paper on phosphatization of soft tissues was published in 1895 [389].
6.3 Investigations Performed from 1900 till 1950

Due to a rapid development of the subject, journal publications of the twentieth century appear to be miscellaneous. Namely,
papers on importance of CaPO4 to bone health [390], as well as further studies on the presence of CaPO4 in urine [391]
were published in 1906 and 1909, respectively, those on the importance of CaPO4 for lactation were published in 1914 [392],
1919 [393], and 1922 [394], on the necessity of CaPO4 in infants food were published in 1913 [395] and 1917 [396],
while the fact that the optimum Ca/P ratio in a diet is the same as that found in human bones or in mother’s milk has been
known since, at least, 1930 [397]. Within 1908–31, Th. Gaßmann from Zürich published a set of papers devoted to investigations
on the composition of teeth and bones [184,185,398–406]. Next available studies on the behavior of undisclosed CaPO4 in
organisms were in print in 1912 [407] and 1921 [408], followed by a study on deposition of CaPO4 and calcium carbonate in
bone and in areas of calcification [409]. In 1926, an important discovery of the apatitic structure of the CaPO4 of bones and teeth
was made by X-ray diffraction [410]. Those results were confirmed and further developed in 1929 [411], 1931 [206,412], 1932
[413,414], 1933 [415], and afterwards [416,417]. The earliest found X-ray diffractograms of various Ca-containing compounds
(orthophosphates, carbonates), as well as bones and teeth are shown in Figure 7, based on which the following conclusions were
made [412]:
“1. x-Ray spectrograms of bone indicate that it has a crystalline structure.

2. Estimations of the spacing between the planes and the intensities of the lines indicate that bone has a crystal structure
fundamentally the same as that of other members of the apatite series.
3. Since chemical analysis indicates that the chemical composition of untreated bone is similar to that of the mineral dahlite
and since x-ray spectrograms indicate the similarity in the crystal structure of bone enamel and dahlite, it is concluded that the
calcium salts of bone and enamel may be represented by the formula: CaCO3 þ nCa3(PO4)2, where n is not less than 2 nor greater
than 3.
4. No evidence is found that CaHPO4 or CaCO3 exists in bone or teeth as such.
5. Ca3(PO4)2 is crystalline and seems to belong to the apatite series.
6. The unit crystal cells of enamel have a random distribution irrespective of the histological elements, the so called rods and
prisms.
7. The diffraction lines can possibly be accounted for on the basis of a close packed hexagonal lattice which when referred to
orthorhombic axes has the lattice constants: a0 ¼ 20.8 10–8 cm., b0 ¼ 12.0 10–8 cm., c0 ¼ 8.82 10–8 cm” (p. 406). Thereafter,
the bone mineral has been frequently identified as HA.
In 1930, a study on the necessity of normal calcium and phosphorus metabolism was published [418]. Further investigations
on determination of the amounts of dissolved CaPO4 in spinal fluid [419] and serum [420–423] were performed in the 1920s and
Figure 7 X-ray diffraction patterns of various Ca-containing compounds (orthophosphates, carbonates), as well as bones and teeth. Reprinted
from Ref. [412].
afterwards, while those in saliva [424], serum of both pregnant women [425,426] and diseased people [426,427], as well as in
blood [428,429] were made in 1930s. A special study on bone changes in the fetus following the administration of dicalcium
phosphate and viosterol to the pregnant mother was published in 1937 [430].
Concerning the undesirable in vivo formed calcifications, research papers on this subject were kept publishing in 1901 [431],
1906 [96] and 1913 [432]. An important conclusion was made in 1906 [96]: “The composition of the inorganic salts in calcified
areas in the body seems to be practically the same, if not identical, whether the salts are laid down under normal conditions
(ossification) or under pathological conditions” (p. 520). Thus, the great similarity between the CaPO4 of bones and those found
in metastatic calcification was established by 1906.
In 1930s, important investigations on crystal dimensions of biological apatites were started. To the best of my findings, Möller and
Trömel were the first, who performed such studies for teeth. Namely, in 1933, they gave values of B1 mm for the crystal sizes of dental
enamel and B0.1 mm for those of dentin [433]. In 1936, the same researchers studied the crystal orientation in dental enamel [434].
In 1934, another research group gave values of 270 Å for enamel crystals and 240 Å for dentin [435]. Presumably, this was the earliest
evidence of the nanometric dimensions of the biologically formed CaPO4. Further, one should mention on a huge review published
in 1935 [436] and another on bone composition published in 1937 [437] summarizing the available by that time knowledge on
CaPO4 in living organisms. In 1942, the following chemical formulae for the major calcified tissues were published as [438]:
[Ca8.50Mg0.25Na0.19][(PO4)5.07(CO3)1.24](H2O)2.0 for bones, [Ca8.36Mg0.45Na0.16][(PO4)5.34(CO3)0.88](H2O)2.0 for dentine and
[Ca9.48Mg0.18Na0.11][(PO4)5.67(CO3)0.45](OH)1.54(H2O)0.46, for enamel. One should point to both the chemical and the structural
differences found among the calcified tissues because, due to the lack of hydroxyl groups, the CaPO4 of bones and dentine were called
‘a hydrated tricalcium phosphate,’ while that of enamel was called ‘a carbonate hydroxyapatite’ [438]. The subject of hydrated
tricalcium phosphate and location of carbonates in bones and teeth were the hot research topics in the 1940s [200,439].
In 1947, the specific surfaces of bone, apatite, enamel and dentin were measured [440]: “The surface area results on the powders
are amazing. For example, bone ash has about 100 sq. m. of surface/gram. The variation of specific surface between
bone, apatite, dentine, and enamel is of special interest because these were of the same particle size (i.e. 60 mesh). Presumably these
variations revealed differences in the sizes of the submicroscopic crystals of hydroxylapatite” (p. 532). In 1948, the aforementioned
dimensions for the crystal sizes of dental enamel and dentin were updated [441]: “We have determined the apparent particle size in
a few enamel powders and in one dentin specimen and found that there are great differences in particle size in different enamels.
Crystallite thickness ranging from some 600 Å in a fine human incisor to some 250 to 300 Å in human molars has been found.
Figures for enamel from rabbit and beaver were somewhat lower. Enamel particles are uniformly developed in all directions; this
contrasts with the apatite particles in bone which are elongated in the c-axis direction” (pp. 530–531).
To finalize the first half of the twentieth century, one should mention on a big review on the nature of the mineral phase of
bones and teeth, in which the available knowledge on the subject was summarized and discussed [442].
7 Early Attempts to Treat Various Diseases by CaPO4
Attempts to treat various diseases by CaPO4 have been known since, at least, 1797 and, initially, they were devoted to treat rickets
(rachitis). For example, let me quote an extract from “a memoir written by Citizen Bonhomme, on the nature and treatment of
rachitis” [443]: “He contends, that the calcareous phoſphate, taken internally, is really tranſmitted by the lymphatic paſſages, and
contributes to oſſification ; and that the internal uſe of the calcareous phoſphate, whether alone or combined with the phoſphate
of ſoda, powerfully contributes to reſtore the natural proportions in the ſubſtances of the bones, and accelerate the cure of rachitis.
In proof of theſe opinions, he relates various experiments made on young fowls, ſome of which took a proportion of calcareous
phoſphate with their food. After an exact compariſon, there could, he tells us, be no doubt of the efficacy of calcareous phoſphate,
in favoring the progreſs of oſſification” (pp. 397–398). Further details on this topic became available by 1804 [40]: “In medicine it
has begun to be preſcribed in the Rachitis, to diminiſh the effects of acids which ſoften the bones, &c” (p. 346) and 1819 [46]: “4.
Phosphate of lime has been employed as a remedy in rickets, a disease in which there appears to be a deficiency of this salt
deposited in the bones. Its usefulness in this disease may be considered rather doubtful, unless the digestive powers of the system
should be improved at the same time” (p. 327).
However, the earliest accessible journal articles on this topic were in print in 1851 [363,364]. The author performed a thorough
study on the biomedical influence of phosphate of lime that was “taken with the breakfast, dinner, and supper, in order to have it
mixed as well as possible with the food taken” on treatment of various diseases. According to the author [363]: “… the phosphate
of lime proved most beneficial in children who suffered from scrofula, diarrhoea, ulcerations and excoriations of the skin and the
bowels, general waste of the cellular tissue, loss of power, &c. In these cases, the mere use of six to ten grains per diem was often
quite sufficient to effect the cure, and I have met with such striking and satisfactory results, as to leave no doubt that the want of the
phosphate of lime was the real cause of the symptoms alluded to” (p. 434, left column). Furthermore, the author stated [363]: “As
to other affections, in which I have tried the phosphate of lime, I have to mention rickets, caries, inflammations, and consecutive
abundant suppurations of the cellular tissue, and also fractures of the bones. In all these cases, the administration proved most
beneficial, and I would strongly advocate its further experimental use. With respect to fractures of the bones, I have to state in
particular, that the consolidation of the callus took place in a much shorter period than is generally the case; however, too large
doses of phosphate of lime must be shunned in these cases, as I have observed an abundant callus, causing a deformity of the
bones, produced by the daily administration of twenty-four grains of the phosphate for a fortnight” (p. 434, right column). In the
second paper, the same author mentioned an interesting misconception that “phosphate of lime contained in a certain quantity of
blood” might be partly “originated from the wear and tear of the bones and the muscular tissue.” Let me quote [364]: “Supposing
now the wear and tear of bones to be abnormally increased, an abnormal quantity of phosphates will consequently re-enter into
the composition of the blood, and by analysing the latter we shall find an increased quantity of phosphates in it. The general waste
of bones is therefore leading to an increase of the phosphates in the blood, and nothing really would be more erroneous, than to
suppose the general quantity of phosphates in the system to be increased, whenever we find their quantity increased in the blood”
(p. 668, right column). The readers are strongly advised to get through the both papers to rediscover the medical ideas and
approaches published over 160 years ago!
The next available medical study involving CaPO4 was published in 1852 [444], followed by studies of 1871 [445] and 1874
[446]. An interesting idea to cure cancer “by embedding a piece of bone material or calcium phosphate in a cancer and exposing it
to a pencil of X rays …” to create a secondary radiation in CaPO4 (either natural or implanted ones) was announced in 1913 [447].
Strange enough, but seeking in the scientific databases for information on farther development of this idea has resulted in the zero
publications (researchers introduced radioactive isotopes of other chemical elements instead [448–451]). Nevertheless, this might
be a worth reinvestigating approach.
The value of phosphorus and calcium in asthma, hay fever and allied diseases was investigated in 1928 [452], while the studies
on addition of CaPO4 to forage of animals have been known for a long time [453]: “While feeding experiments dealing with
mineral supplements date from the work of Chossat (1) in 1842, the experimental evidence in which we are primary interested
occurs after 1900” (p. 303). Afterwards, the author that publication described in details the results of the studies performed within
1904–1930 [453].
To finalize this section, let me mention that application of CaPO4 as caking inhibitors has been known since, at least, 1933
[454], while that for filtration of sugar liquors has been known since, at least, 1942 [455]. Since all these topics are beyond the
scope of this review, the interested readers are requested to study the original publications for details.
8 CaPO4 as Bone Grafts
8.1 Artificial Grafts in the Nineteenth Century and Before

The artificial generation of tissues, organs or even entire living organisms has been a matter of myths and dreams throughout the
history of humankind. Unfortunately, due to the practice of cremation in many societies, little is known about the prehistoric
materials used to replace bones lost to accident or disease. Nevertheless, according to the available literature, introduction of non-
biological materials into the human body was noted far back in prehistory. Namely, according to Ratner [456]: “The remains of a
human found near Kennewick, Washington, USA (often referred to as the “Kennewick Man”) was dated to be up to 9000 years old.
That individual, described by archeologists as a tall, healthy, active person, wandered through the region now known as southern
Washington with a spear point embedded in his hip. It had apparently healed in and did not significantly impede his activity. This
unintended implant illustrates the body’s capacity to deal with implanted foreign materials. The spear point has little resemblance
to modern biomaterials, but it was a tolerated foreign material implant, just the same. Another example of the introduction of
foreign materials into the skin, dated to over 5000 years ago, is the tattoo. The carbon particles and other substances probably
elicited a classic foreign-body reaction” (p. xli).
Later, man’s attempts to repair the human body with the use of implant materials were recorded in the early medical writings of
the Hindu, Egyptian, Etruscan and Greek civilizations. The earliest successful implants were in the skeletal system. Namely,
applying modern pathology methods to a B3000-year-old mummy, researchers at Ludwig Maximilians University, Munich,
showed that ancient Egyptian physicians designed wooden prostheses to help their ailing patients: in that case, a 50–60-year-old
woman whose toe was amputated (Figure 8). Besides, the famous painting by Fra Angelico (ca.1395–1455) “The Healing
of Justinian by Saint Cosmas and Saint Damian” (Figure 9) a visualization of the legend of twins Sts. Cosmas and Damien
(died ca. AD 287) depicting a transplantation of a homograft limb onto an injured soldier, is one early instance of the vision of a
regenerative medicine.
Historically, a selection of the materials was based on their availability and an ingenuity of the individual making and applying
the prosthetic [457]. Archeological findings exhibited in museums showed that materials used to replace missing human bones
and teeth included animal or human (from corpses) bones and teeth, shells, corals, ivory (elephant tusk), wood (Figure 8), as well
as some metals (gold or silver). For instance, ‘the father of Western medicine’ Hippocrates (ca.460 BC–ca.370 BC) apparently used
gold wire and linen thread for ligatures in the repair of bone fractures. Aulus Cornelius Celsus (ca.25 BC–AD 50) recommended
the filling of large cavities with lint, lead and other substances before attempting extraction to prevent the tooth from breaking
under the pressure of the instrument. This may have been the beginning of filling materials for carious teeth. The Etruscans learned
to substitute missing teeth with bridges made from artificial teeth carved from the bones of oxen, while in ancient Phoenicia loose
teeth were bound together with gold wires for tying artificial ones to neighboring teeth. Popp states that ancient Egyptians also
made artificial ears, noses and eyes [458]. The Chinese recorded the first use of dental amalgam to repair decayed teeth in the year
659 AD, while in Americas the pre-Columbian civilizations used gold sheets to heal cranial cavities following trepanation [459].
Besides, while excavating Mayan burial sites in Honduras in 1931, archeologists found a fragment of mandible of Mayan origin,
dating from about 600 AD. This mandible, which is considered to be that of a woman in her twenties, had three tooth-shaped
pieces of shell placed into the sockets of three missing lower incisor teeth. In 1970, a Brazilian dental academic Prof. Amadeo
Bobbio studied the mandible specimen and took a series of radiographs. He noted compact bone formation around two of the
implants, which led him to conclude that the implants were placed during life [460]. This might be the first recorded use of dental
implants. More to the point, an iron dental implant in a corpse dated B200 AD was found in Europe. That implant was also
described as properly bone integrated [461].
In the middle ages, one of the first scientific descriptions of congenital and acquired defects of the maxilla and their treatments
was given by the famous French barber surgeon Ambroise Paré (ca. 1510–1590), who is considered as one of the ‘fathers of surgery
and modern forensic pathology.’ In 1564, he published Dix livres de la chirurgie, avec le magasin des instrumens necessaires à icelle,
where he specifically described defects of the palate with bone destruction caused by arquebus shots, stab wounds or syphilitic
Figure 8 A wooden prosthesis of a hallux of a mummy.
Figure 9 Fra Angelico (ca. 1395–1455) ‘The healing of Justinian by Saint Cosmas and Saint Damian’ (approx. 1439) is exhibited at Museo di San
Marco, Florence, Italy.
gumma, describing also the accompanying speech deficiency and giving general principles of treatment. He used a flat, vaulted,
metallic plate in gold or silver with a sponge attached to it. The sponge was introduced into the defect, where it expanded with
readily absorbed nasal and oral secretions, thus holding the obturator base in position. Paré is also credited with having prepared
artificial teeth from bones and ivory. In 1668, a book by a Dutch surgeon Job Janszoon van Meekeren (1611–1666) was published
[462]. One of the most interesting works, performed by van Meekeren, was a reconstruction the face of duke Butterlijn, who
received a piece of dog’s skull-bone to heal his skull defect that was caused by a Tartar sword. The duke recovered well but was
banned by Russian priests, who considered that a combination of a Christian head with a dog bone was unacceptable for the
church. Therefore, although the graft was completely healed, the duke asked the surgeon to remove it again [462].
In the eighteenth century, the first well documented studies on autografts and allografts were published. Namely, the earliest
found journal paper on a clinical use of a bone autograft belongs to the German surgeon and ophthalmologist Philipp Franz von
Walther (1782–1849), who replaced surgically removed parts of a skull after trepanation [463], while the one on a clinical use of a
bone allograft belongs to the Scottish surgeon Sir William Macewen (1848–1924), who successfully reconstructed an infected
humerus of a 4-year-old boy by a graft obtained from the tibia of a child with rickets [464]. Additional historical details on bone
grafts are available in literature [465].
Concerning dentistry, specimens dating back to the eigth century BC indicate Etruscans may have been the first people to
employ orthodontic bands to improve tooth alignment [466]. By the tenth century AD, Muslim dentists became the leaders in
dental surgery and dental restoration [467]. Namely, an Arab dentist, Abu Gaafar Amed ibn Ibrahim ibn abi Halid al-Gazzar, from
North Africa, described methods of dental restoration in his Kitab Zad al-Musafir wa qut al-Hadir (Provision for the traveler and
nutrition for the sedentary), which was later translated into Latin as Viaticum. According to Almahdi [468], al-Gazzar provided the
following treatment for dental caries: “with caries purging must take place first, and then the teeth can be filled with gallnut, dyer’s,
buckthorn, terbinth resine, cedar resine, myrrh, pellitory and honey, or fumigated with colocynthis root” (p. 56). A bit later Ibn
Sina (980–1037), whose name is better known as Avicenna, “filled carious teeth with cypress, grass, mastix, myrrh, or styrax,
among others with gallnut, yellow sulfur, pepper, camphor” (p. 57).
Later, in Europe, a homologous transplantation of teeth in humans became the common method to replace teeth. Namely, a
Scottish surgeon John Hunter (1728–1793) investigated in his pioneering work the effect of transplantation not only at a clinical
level (he claimed, that homologous transplanted teeth lasted for years in the host) but also performed animal experimental work
on the fate of transplants, thereby setting the basis for a scientific approach on transplantation medicine [469]. Here, one should
mention, that various restorative materials might be used for feeling defects, capping exposed pulps and dental cavities. Currently
they include zinc orthophosphate, zinc polyacrylate (polycarboxylate), amalgams, glass ionomer cements, calcium hydroxide, etc.
[470,471]; however, within the scope of this review, CaPO4-based formulations are considered only. According to the available
literature, Dr. Junius E. Cravens (1844–1920) from USA proffered creative concepts in pulp capping in the 1870s. He had the
opinion that dentin-like material would be the best to keep the pulp vital. Therefore, Cravens used a CaPO4 powder, which was
mixed with lactic acid to low viscosity. The result was a soluble calcium lactic orthophosphate, which was applied onto the
exposed pulp tissue [472]. This pulp-capping agent was brought to the market by the S.S. White company with the trade name
‘Lacto-Phosphate of Lime’ (Figure 10). Sugar-containing formulations were known as well [473]. To the best of my findings, that
study by Cravens might be considered as the earliest mentioning on artificial CaPO4-based biocomposites and hybrid biomaterials
(reviewed in Ref. [474]). Thus, one might claim that the grafting history of CaPO4 started in 1870s.
However, in the past, many implantations failed due to various infections, which tended to be exacerbated in the presence of
implants, since they provided a region inaccessible to the body’s immunologically competent cells. Therefore, the use of
implantable biomaterials did not become practical until the advent of an aseptic surgical technique developed by a British surgeon
Sir Joseph Lister (1827–1912) in the 1860s. In addition, there was a lack of knowledge about a toxicity of the selected materials.
Since the major inorganic components of the normal calcified tissues of mammals were established by 1808 [336], application of
CaPO4 and other calcium-containing compounds as artificial bone grafts became logical.
Historically, plaster of Paris (calcium sulfate) was the first widely tested artificial bioceramics. For example, according to Wikipedia,
literature dating back to 975 AD notes that calcium sulfate was useful for setting broken bones. However, those were ex vivo
applications. According to the available literature, by the end of the nineteenth century, surgeons already used plaster of Paris as a
bone-filling substitute [475]. Nevertheless, it was a famous German surgeon Themistocles Gluck (1853–1942), who, amongst his
range of contributions, on 20 May 1890 performed the first well documented ivory (virtually, pure biological apatite) knee repla-
cement bedded in a calcium sulfate based cement, which was followed by a total wrist replacement in another patient 3 weeks later
[476]. Later in 1890, Gluck presented a further case of a total knee replacement to the Berlin Medical Society: at only 35 days after
operation, the patient was pain free with active knee flexion and extension. All the joint arthroplasties performed by Gluck were
remarkably successful in the short term; however, all ultimately failed because of chronic infections [477,478]. After the above-
mentioned case of lacto-phosphate of lime (Figure 10), this seems to be the second well-documented grafting application of CaPO4.
To conclude this part, one should stress that the performance of living tissues is the result of millions of years of the evolution,
while the performance of the acceptable artificial substitutions those humankind has designed to repair damaged tissues is only a
few decades old. This explains the greatest differences between them. To get the historical perspective on the development of
artificial grafts prepared from other materials, the interested readers are referred to other publications [13,15–18,465,479–483].
8.2 The Twentieth Century

According to the previous section, the initial attempts to use CaPO4 for grafting purposes were performed in the end of the
nineteenth century. However, in the aforementioned cases, either the biomedical applications of biologically produced CaPO4
(Gluck) or dental applications, not requiring any surgery (Cravens) were described. According to both the electronic databases and
previous reviews on the subject [13,15–18,465,479–483], the first attempt to implant a laboratory produced CaPO4 (it was TCP)
as an artificial material to repair surgically created defects in rabbit bones was performed in 1920 [14] by the US surgeon Fred
Houdlette Albee (1876–1945), who invented bone grafting [484] and some other advances in orthopedic surgery. The researchers
injected either 0.5 or 1 c.c. of 5% slurries of TCP in distilled water (which was then sterilized for three successive days in the Arnold
sterilizer, at 60 1C) into surgically created radial bone gaps of rabbits, leaving the periosteum intact [14]. Radiographic analysis
Figure 10 An advertisement of the S.S. White company for ‘Lacto-Phosphate of Lime’ 1873. Reprinted from Dent. Cosmos 1873, 15, 683.
revealed that the TCP injected defect demonstrated more rapid bone growth and union than the control. The average length of
time for bony union with TCP was 31 days, compared to 41 days for the controls. No appreciable bone growth was stimulated by
injecting TCP beneath the periosteum in non-defective radii or into subcutaneous tissues. Although this seems to be the first
scientific study on use of an artificially prepared CaPO4 for in vivo repairing of bone defects, it remains unclear whether that TCP
was a precipitated or a ceramic material and whether it was in a powder or a granular form. Unfortunately, the researchers
published nothing on this topic. In 1927, Hey Groves (1872–1944) described pure ivory hip hemi-arthroplasty for fracture [485].
In 1931, Murray also reported an acceleration of healing following implantation of calcium salts composed of 85% TCP and 15%
CaCO3 in canine long bone defects [486,487].
At the beginning of 1930s, the classic osteoinductive phenomenon was defined well by Huggins [488], who demonstrated that
autoimplantation of transitional epithelium of the urinary bladder to abdominal wall muscle in dogs provoked ectopic bone
formation. A bit later, Levander demonstrated that crude alcoholic extracts of bones induced a new bone formation when injected
into muscle tissue [489,490].
Simultaneously, in 1930s, Haldeman and Moore [491], Stewart [492], Key [493], and Shands [494] discovered the fact that
only certain types of CaPO4 mentioned in Table 1 really influence the bone healing process. Namely, Haldeman and Moore
implanted various types of CaPO4 such as MCP and DCP (it remains unclear whether they were in hydrated or anhydrous forms),
TCP, as well as calcium glycerophosphate as dry powdered salts into 0.5–1.0 cm defects in radii of 17 rabbits, while the opposite
side served as control. Radiographic analysis demonstrated that in no case did the presence of MCP, DCP or calcium glycer-
ophosphate had a favorable influence on a delayed healing compared to the control, while the presence of TCP at the site of the
fracture appeared to favor the union [491]. Furthermore, Key [493] suggested that “if a defect in bone could be filled by a non-
irritating, slowly soluble mass, which was porous and which contained calcium phosphate and carbonate in a form in which they
could be resorbed, it would be reasonable to expect osteoblasts to invade the mass, utilize the calcium, and build new bone which
would replace the mass of calcium and cause the bone to be restored to its original form. The ideal material would appear to be
rather dense cancellous bone from which a large percentage of the organic material had been removed” (p. 176). However, Key
found that “Neither calcium phosphate and carbonate in the proportions in which they occur in bone, nor bone powder, made by
removing the organic matter from bone, appear to stimulate osteogenesis of bone when implanted in a bone defect” (p. 184).
Stewart [492] concluded that “1. Lime salts and boiled bone when placed into a bone defect with either traumatized muscle or
fascia do not serve as a source of available calcium resulting in supersaturation of connective tissue and regeneration of missing
bone. 2. Live bone chips placed in bone defects regenerate the missing bone” (p. 871). Shands [494] also reported conflicting
effects of several calcium salts (calcium glycerophosphate, a mixture of TCP (3 parts) and CaCO3 (1 part), bone ash and calcium
gluconate) on bone repair. Namely, in defects in the ulna of dogs, the investigated calcium salts appeared to stimulate bone
formation, while in operations upon the spine, calcium glycerophosphate did not stimulate bone formation and appeared rather
to exert an inhibiting influence. In 1948, Schram and Fosdick confirmed the fact that only certain types of CaPO4 influence the
bone healing process [495]. Similar conclusions were obtained in 1951 by Ray and Ward [496].
Due to the reasons, mentioned in the abstract, the historical events of the second half of the twentieth century are reported very
briefly. Namely, in 1945, the earliest publication devoted to applications of CaPO4 as dentifrices was published [497]. Two
important CaPO4-containing simulating solutions, namely, Earle’s balanced salt solution (EBSS) [498] and Hanks’ balanced salt
solution (HBSS) [499], became known in 1943 and 1949, respectively. In 1950, the history of self-setting CaPO4 formulations was
started [500]. The author of that important publication investigated mixtures of both oxides and hydroxides of various metals with
aqueous solutions of orthophosphoric acid and discovered a number of cold-setting formulations. For example, he found that
CaO, sintered at 1100 1C, did not set in H3PO4, while that in liquid containing 9.6% CaO was found to set after B12 h in
presence of H3PO4 [501]. The latter mixture might be considered as the first prototype of the self-setting CaPO4 formulations
(reviewed in Ref. [501]). The next publications on this topic appeared in 1975 [502] and 1976 [503]. In the latter study, the
authors implanted porous cylinders prepared from mixtures of 80% TTCP þ 20% MCP, 80% TCP þ 20% MCP and 80%
DCP þ 20% MCP (it is unclear whether MCP and DCP were hydrated or not and whether a- or b-TCP was used), which could have
possessed some self-setting abilities. Therefore, the study by Köster et al. [503] could probably be considered as the first biomedical
application of the self-setting CaPO4 formulations. However, the real history of this subject started in 1982 [504,505].
The modern history of ACP [76] began in 1955 [506], while, in 1960, the first mentioning on CDHA in the publication’s title
occurred [507]. In 1963, an important study on HA preparation was published [508], while, in 1964, the crystal structure of HA
was refined [509]. In 1965, thorough investigations of carbonated apatites were started [510]. In 1969, an important paper on a
forming method of HA prostheses was published [511], in which the authors hot-pressed HA power into dense and useful shapes.
That study might be considered as the earliest one on the fabrication of CaPO4 implants (reviewed in Ref. [512]). In 1971, the first
study on preparation of biodegradable porous b-TCP scaffolds was published [513]. Therefore, it is not surprising that the term
‘bioceramics’ has been introduced simultaneously. Namely, according to the available databases, the first paper with the term
‘bioceramics’ in the abstract was published in 1971 [514], while the earliest papers with that in the title were published in 1972
[515,516]. However, application of the ceramic materials as prostheses had been known before [517–520]. Also, in 1972 [521]
and 1973 [522], the first publications on lunar apatites were published. In 1973, the work of Graham and van der Eb showed the
first application of CaPO4 in condensation of genetic materials [523]. The researchers demonstrated that CaPO4 could condense
DNA and increase the transfection efficiency with a relatively simple procedure. In addition, in 1973, the first study on preparation
and implantation of resorbable and porous CaPO4 (it was b-TCP) bioceramics was published [524]. Besides, in 1973, an
important book by McConnell was published [4]. In 1975, the modern dental application of CaPO4 began. Namely, b-TCP was
applied both in surgically created periodontal defects [525] and as an adjunct to apical closure in pulpless permanent teeth [526],
followed by a study of 1979, in which dense HA cylinders were used for immediate tooth root replacement [527]. On April 26,
1988, the first international symposium on bioceramics was held in Kyoto, Japan.
The history of CaPO4 coatings, films and layers (reviewed in Refs. [528,529]) started in 1976 [530], while that of CaPO4 based
biocomposites and hybrid biomaterials (reviewed in Ref. [474]) started in 1981 [531,532]. An extensive commercialization of the
dental and surgical applications of CaPO4 (mainly, HA) bioceramics occurred in the 1980s, largely due to the pioneering efforts by
Jarcho [533–536] in the USA, de Groot [537–539] in Europe and Aoki [540–543] in Japan. Shortly afterwards HA has become a
bioceramic of reference in the field of CaPO4 for biomedical applications. The early commercial trademarks, composition,
producers and year comprised: Synthograft/Synthos (b-TCP) – Miter Inc./J&J (1975), CEROS 80 (HA) – Mathys (1980), Dur-
apatite (HA) – Cook-Waite (o1981), ProOsteon (coralline HA) – Interpore (1981), Alveograf (HA) – Cook-Waite (1982),
Calcitite (HA) – Calcitek (1982), CEROS 82 (b-TCP) – Mathys (1982), BioBase (a-TCP) – Zimmer (1982), Periograf (HA) – Cook-
Waite (o1983) [544]. As seen from this list, preparation and biomedical applications of apatites derived from sea corals [545–
547] and bovine bone [548] were already known [549]. In 1985, the first publication on drug-loaded CaPO4 bioceramics [550], as
well as those on biphasic, triphasic and multiphasic CaPO4 formulations (reviewed in Ref. [551]) were published [552,553]. In
1990, the first version of simulated body fluid (SBF) was introduced [554], while the history of nanodimensional and nano-
crystalline CaPO4 (reviewed in Ref. [555]) started in 1994 [556–560]. Finally yet importantly, also in 1994, the first paper on use
of CaPO4 as scaffolds was published [561], while applications of CaPO4 in tissue engineering began in 1998 [562–564].
To finalize the twentieth century, it is important to mention the early books on the biomedical applications of CaPO4. The
earliest collected book of 1983 was edited by de Groot [539], followed by a book of 1984 edited by Misra [565], while three most
important monographs on the subject were published in 1991 by LeGeros [566] and Aoki [567], followed by one published in
1994 by Elliott [568]. To get further details on the recent history of CaPO4, bioceramics and biomaterials in general, the interested
readers are referred to other reviews on the subject [13,15–18,465,479–483].
9 Conclusions
To finalize this review, let me quote Wikipedia once again: “Historians write in the context of their own time, and with due regard
to the current dominant ideas of how to interpret the past, and sometimes write to provide lessons for their own society” [12].
Therefore, all the aforementioned historical facts, discoveries, theories, concepts, misconceptions and approaches are treated
according to current (AD 2015) level of knowledge on CaPO4. Thus, it is important to bear in mind that the reported treatment of
the historical facts and events might be reconsidered in future due to both new discoveries and updated points of view. Never-
theless, some solid statements can be made.
The subject of apatites and other types of CaPO4 has been investigated for almost 250 years. This was a long period of great
discoveries and impressive mistakes, original concepts and interesting misconceptions, excellent experiments and various
unfortunates initially of the calcified tissues only and afterwards of the chemically CaPO4. All these years were spent on gaining the
initial knowledge on the subject, followed by its further clarification, extension and development. These eventful years were full of
daily and routine hard work performed by many excellent and of moderate abilities scientists and researchers, students and
assistants, technicians and participants, the vast majority of whom even have not been mentioned in this review. Nevertheless, by
1950, the combined long-term efforts of all these often unknown early investigators created the solid background for a real
explosion of science, technology and biomedical applications of CaPO4 that started in 1960s and continuously prospers up to
now, which, finally, resulted in the current state-of-the-art.
As seen from the aforementioned, the substantial amount of currently available scientific facts and experimental approaches appear
to have been known for very many decades and, in fact, the considerable amount of relatively recent investigations on CaPO4 is just
either a further development of the earlier studies or a rediscovery of the already forgotten information. Since the first commercially
produced artificial bone grafts and other types of CaPO4-containing biomaterials appeared just a few decades ago [533–544], a
reasonable question arises: why did it take so long (almost 200 years) to translate the initial knowledge into practice? Presumably, this
is a matter of the technological development because both the biomedical and mechanical properties of even the most advanced
formulations are still unsatisfactory and incomparable with those of natural bones and teeth. Hopefully, this overview provides the
historical necessary background that will keep encouraging natural scientists, engineers and clinicians to rethink and reinvestigate the
already forgotten and poorly known facts and approaches for further development of CaPO4-based formulations.
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A History of Calcium Orthophosphates (Capo) From 1770S Till 1950

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A History of Calcium Orthophosphates (CaPO4) from 1770s till 1950

SV Dorozhkin, Moscow, Russia

Reference Module in Materials Science and Materials Engineering doi:10.1016/B978-0-12-803581-8.04089-3 1

Table 1 Existing CaPO4 and their major properties [1,2]

0.5 Monocalcium phosphate monohydrate Ca(H2PO4)2 H2O 1.14 B18 0.0–2.0

or DCP), mineral monetite

1.5 b-Tricalcium phosphate (b-TCP) b-Ca3(PO4)2 28.9 B0.0005 a

1.2–2.2 Amorphous calcium phosphates (ACP) CaxHy(PO4)z nH2O, n ¼3–4.5; b b

TetCP), mineral hilgenstockite

2 General Deﬁnitions, Major Problems and Limitations

3 Investigations and Knowledge at the ‘Pre-CaPO4’ Time

4 Investigations and Knowledge on CaPO4

4.1 In the Eighteenth Century

4.2 In the Nineteenth Century

8CaCl2 þ 5Na4 H2 P2 O8 ¼ Ca8 H2 P6 O24 þ 16NaCl þ 2Na2 H4 P2 O8 ” ðp: 300Þ

Ca3 ðPO4 Þ2 þ 2H2 SO4 ¼ CaH4 ðPO4 Þ2 þ 2CaSO4

CaH4 ðPO4 Þ2 ¼ CaðPO3 Þ2 þ 2H2 O

CaðPO3 Þ2 þ 10C ¼ P4 þ Ca3 ðPO4 Þ2 þ 10CO” ðp: 460Þ

4.3 From 1900 till 1950

Figure 3 The system CaO–P2O5–H2O in 1908. Reprinted from Ref. [177].

Fluor-apatite, Ontario I 9.3670.01 6.8870.01 0.7350 522

5 Early Publications on CaPO4 of the Geological Origin

Carbonic acid 1 grain.

Frances. Are they very different from each other?

6 Studies on CaPO4 in Living Organisms

6.1 Investigations Performed in the Eighteenth Century

6.2 Investigations Performed in the Nineteenth Century

Enamel of Human Teeth.

Osseous Part of the Teeth of the Ox.

Commercial bone-ash Pure ox bone-ash

Moisture and volatile matter 6.70 1.86

Phosphate of lime 1 805

6.3 Investigations Performed from 1900 till 1950

“1. x-Ray spectrograms of bone indicate that it has a crystalline structure.

7 Early Attempts to Treat Various Diseases by CaPO4

8 CaPO4 as Bone Grafts

8.1 Artiﬁcial Grafts in the Nineteenth Century and Before

Figure 8 A wooden prosthesis of a hallux of a mummy.

8.2 The Twentieth Century

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