FORMULATION DEVELOPMENT

AKASH KUMAR GUPTA, ABHAY KUMAR, ANKIT JAISWAL

INTRODUCTION

 As is the case with other pharmaceuticals, formulation development is one of the critical steps
in developing a protein as a therapeutic product. Development of stable protein formulations
may require even more resources and effort than conventional small molecule pharmaceuticals.
Proteins typically have more stability issues as a result of their complexity and delicate structural
stability. Fortunately, a great deal of research regarding protein stability has been conducted
and this information is readily available in the literature (reviewed by Wang and Hansen, 1988;
Manning et al., 1989; Chen, 1992; Ahern and Manning, 1992a, 1992b; Arakawa et al., 1993;
Cleland et al., 1993; Wang and Pearlman, 1993; Pearlman and Wang, 1996; Volkin and
Middaugh, 1997). Ultimately, it would be ideal to be able to develop a pure pharmaceutical
containing only the native protein. However, it is not practical to have only the native form of a
protein in the formulation because the protein must be purified from a complex biological
mixture containing a pool of other proteins which includes misfolded, denatured, and degraded
forms of the same protein. Furthermore, a major challenge is to maintain the integrity of the
purified protein during routine pharmaceutical processing, storage, handling, and delivery to the
patient. One could envision achieving this goal by developing a formulation with perfect
stability, i.e., no physical and chemical change in the protein. Because proteins are complex
molecules composed of numerous reactive chemical groups and delicate three-dimensional
structures, identifying a set of conditions to keep all components stable is virtually impossible. In
general, commercial therapeutic protein formulations are developed under the assumption that
some degree of physicochemical changes will occur during storage and handling.
 Realizing that it is impossible to develop a perfectly stable formulation, especially while meeting
an aggressive product development timeline, the main objective then becomes one of
maintaining the appropriate safety and efficacy of the product. In order to achieve this
objective, it is imperative to understand the broad spectrum of degradation pathways affecting
proteins, and to have available equipment and expertise in an extensive 2 repertoire of
analytical methods. Formulation development focuses on determining the potential degradation
pathways, assessing the significance of each and optimizing variables to minimize the
degradation products that are clinically significant.
 In addition to insight into the scientific and regulatory issues, developing commercial
formulations requires a clear understanding of the potential market. For example, indication,
patients, method of delivery, frequency of dosing, typical dose requirement, market distribution
and other business-related information will provide directions for the design of a successful
formulation. Also, it is important to consider the competitiveness of the formulation as
compared to other products available in the market.
 In this chapter, an overview of critical factors affecting the design of therapeutic protein
formulations and a general guide to developing commercially viable dosage forms for protein
 pharmaceuticals will be discussed. Since the majority of practical issues are not covered very
well in the scientific literature, this chapter also includes information from regulatory guidance
documents (see Appendix), labels from marketed products and routine industrial experience,
 Pharmaceutical solids may come in contact with water during manufacturing processes and
some moisture could remain as the residual water from processing in solid oral dosage forms.
Moreover, they may be exposed to water during storage at high relative humidity (RH) or in a
dosage form consisting of materials that contain water and are capable of transferring it to
other ingredients.1 The physical and chemical properties of pharmaceutical solids are critically
dependent on the presence of moisture, for example, flow, compaction, dissolution, stability,
storage, processing into formulations, and final product packing.2 The association between
moisture and solid materials was described as one in which the moisture is adsorbed as
monolayers or multilayers or may be present as condensed water at the surface.3 Water can
interact with crystalline solids by adsorption of moisture on particle surfaces, crystal hydrate
formation, deliquescence, and capillary condensation.4 In contrast, amorphous materials have a
high capacity for water vapor sorption, that is, the amount of water absorbed is greater than
what could be accounted for only by surface adsorption and thus the bulk properties of the solid
can be significantly altered. The amount of water that is sorbed is dependent on the chemical
properties and polarity of the compound, as well as on the RH, temperature, and particle-size
distribution, specific surface area, and deliquescence, structure of the sorbent surface, and
porosity of the material. For these reasons information on the sorption mechanism of water on
powder surfaces is required. This information can often be obtained from the shape of the
vapor sorption isotherm. Moisture sorption isotherms characterize the amount of vapor
adsorbed or desorbed at different equilibrium concentrations in the gas phase. Isotherm
equations are useful for predicting the water sorption properties of excipients, but not even one
equation gives results accurate throughout the entire range of water activities. The BET
equation (Brunauer–Emmett–Teller’s multilayer adsorption theory) was developed based on the
fact that sorption occurs in two distinct thermodynamic states—a tightly bound portion and
multilayers having the properties of bulk free water.

PREPARATION FOR FORMULATION DEVELOPMENT

Resource requirements for formulation development

A list of resources that should be available before starting formulation development is summarized
in Table 1. Some resources may not be as critical as others, depending on the nature of problems
encountered, but it is important to have sufficient resources to discover major formulation issues as
early as possible in the product development process. Without the appropriate equipment and
personnel, the development of an acceptable formulation can be greatly hampered, potentially to
such a degree that the product is never brought to market. Of course, not all of the resources need
to be at the company developing the therapeutic protein, but if outside contractors are employed it
is essential that timely access to resources is available. In addition, the quality of raw materials
should be carefully evaluated because unexpected impurities may introduce unnecessary
complications in the stability profile that is determined during formulation development and testing.
Useful information for designing formulation

The configuration of a protein formulation is affected by how the drug will be used as a product. If such
information is available when designing formulation studies, it is recommended to consider the
limitations and challenges associated with each application. Examples of such information are listed in
Table 2.

PREFORMULATION DEVELOPMENT

It is important to understand the critical properties of a protein before starting large studies to design
and test the final formulation. Preformulation studies are designed to learn about the protein’s
susceptibility to a variety of pharmaceutically relevant stresses. The main objectives of preformulation
research include: general characterization of the product; investigation of potential stability issues;
development of relevant analytical methods; establishment of a stability profile with stability-indicating
assays; and identification of major formulation challenges. A summary of these issues will be presented
in this section.

Accelerated stability studies

In order to predict potential stability problems within a short period of time and to develop appropriate
analytical methods, proteins are exposed to stronger-than-real stresses and various degradation
products induced by the stresses are examined. The results obtained from these so-called "accelerated
stability studies" might also be useful to predict the kinetics of the degradation processes under real
handling conditions, when there are not sufficient real-time results available because of time and
resource constraints. However, the accelerated stability study is not acceptable to determine expiry of
the product, so it is best used to rank order the importance of different degradation pathways.
Approaches and cautions in the extrapolation of data from accelerated stability testing to real-time
stability and normal handling conditions are discussed in detail below. Conditions to accelerate various
degradation reactions in protein products and potential problems to monitor are listed in Table 4.
Proteins contain numerous amino acid side chains and delicate three-dimensional structures, which can
be susceptible to different 5 stresses. Therefore, it is important to test the protein under a variety of
physical and chemical stresses in order to provide a good simulation of the degradation products that
can be generated.

Evaluation of the significance of problems

As stated earlier, it would be ideal to have a pure protein in an absolutely stable formulation. In reality,
however, scientists have to design formulation based on compromises that deal with several different
potential problems. To make matters worse, the formulation needs to be recommended long before it is
evaluated fully, because of typical aggressive timelines in the industry. In general, the formulation will
have to be optimized based on assumptions and extrapolations of results obtained during a limited time.
Therefore, it is important to utilize the given time efficiently, by collecting as much relevant information
as possible for evaluating the significance of each problem. 7 Due to the marginal stability of proteins, it
is possible to create rapidly a variety of degradation products during accelerated stability testing.
However, not all the degradation products that are observed will be significant under normal handling,
shipping and storage conditions. Furthermore, the rank order of different degradation processes under
accelerated stability testing will NOT be the same under practical handling conditions, because each
reaction has a different stress dependency, i.e., reaction order and activation energy. Another important
thing to keep in mind when evaluating different degradation processes is the contribution to the
pharmaceutical quality of the product. Critical degradation products should be designated not on the
quantity obtained during accelerated stability studies, but on a comprehensive understanding of their
contributions to the quality of the product

FORMULATION DEVELOPMENT

As discussed above, the critical parameters affecting the pharmaceutical quality of a protein therapeutic
are defined during the preformulation studies. In formulation 9 development, the effects of formulation
variables on the defined critical parameters are examined to optimize protein stability. Which variables
are most important depends of the formulation type chosen. For example, resistance to agitation and/or
accidental freezing is a critical property for an aqueous formulation, which would not be a concern for a
lyophilized formulation. Similarly, choosing excipients that provide a glassy matrix to stabilize the
protein is only a concern for dried formulations

Liquid formulations.

It is important to understand that developing conditions to keep proteins stable in a liquid form for a
pharmaceutically relevant storage time (e.g., two years) is not a simple task. For most proteins, including
relatively stable ones, at least some degradation should be expected even during refrigerated storage.
Unless there is strong evidence supporting that the protein remains stable for two years and the
evidence is supported by a broad spectrum of analytical methods, one needs to be very careful about
the final decision to market a liquid formulation. Physical or chemical changes that have low activation
energy should be monitored especially carefully under real storage conditions. If there is a degradation
product that can significantly affect the pharmaceutical quality at its minimum concentrations (e.g.,
formation of particulates) great care must be taken to assure that such a product does reach
unacceptable levels during realtime storage. If long-term storage studies are not implemented until late
in the product development process, there is a risk that problems due to unacceptable levels of
degradation products will not be discovered in time to test alternative formulations. In addition to
stability during storage, temporary exposure to temperatures outside the recommended conditions
should also be tested because it can affect the quality of the drug. Also, results obtained from multiple
freeze-thawing cycles will be useful to determine if the formulation can accommodate unexpected
freezing during distribution and storage. Likewise, sensitivity to agitation or surface denaturation needs
to be understood to support formulation choices as well as shipping and handling guidelines. For
formulations containing low protein concentration, special attention is required to avoid impurity-
related stability issues (e.g., oxidation fostered by metal contaminants in excipients).

Solid dosage forms.

Recent improvements in devices designed for easier use of lyophilized products, e.g., dual chamber
syringes, dual chamber cartridges and convenient reconstitution devices, have helped pharmaceutical
industries to develop lyophilized products without too many concerns surrounding patient compliance
issues. Because 10 lyophilized products have less stability-related issues and have a much greater
potential tolerance for room-temperature storage, many biopharmaceutical industries consider the
lyophilized formulation as a default option. In fact, lyophilization has been widely utilized to overcome
various stability issues of labile proteins. However, it is important to note that lyophilization can present
its own challenges, particularly in designing appropriate formulations and economic drying cycles.
Detailed discussion about the rational design of stable lyophilized formulations is available in another
chapter in this book.

In addition to the required stability, a successful lyophilized formulation should also have the desired
physical properties of the dried powder, e.g., ruggedness of the cake and the maintenance of the
physical states for each of the ingredients. For example, crystallization of an initially amorphous
excipient during storage can lead to unacceptable degradation of the protein product. Furthermore,
optimal water content for protein stability should be studied and controlled during storage. It is
preferable to define an acceptable range of water contents to provide flexibility in the manufacturing
process. To assure that the appropriate water content is maintain, the integrity of container/packaging
should be monitored in a high relative humidity environment.

The identity and volume of the reconstitution medium should also be clearly defined, because the use
of injectable fluids other than the recommended one may compromise the quality of the product (e.g.,
solution tonicity or protein stability). Reconstitution should be convenient and rapid, and the stability of
the reconstituted solution during handling and delivery needs to be demonstrated.

Only recently have spray-dried formulations become commonly used with the advent of novel protein
delivery technologies. For example, spray-dried powders have been useful for developing products that
require uniform particle size (e.g., pulmonary inhalation for systemic delivery). Similar issues to the
lyophilized formulation apply to the spray-dried formulation, and the details of development of spray-
dried formulations are presented in another chapter in this book. In addition to protein stability,
physical properties pertinent to powder processing and powder stability (e.g., flowablity, hygroscopicity,
agglomeration, density and crystallization of excipients) need to be well characterized.

Single Dose and Multidose Forms.

Most protein pharmaceuticals are marketed as single dose forms. However, multidose formulations are
useful when the dose needs to be split (e.g., dose titration or dose combination). Multidose
formulations are distinguished by the presence of preservatives in the formulation, which prevent
microbial contamination and/or growth during multiple disruptions of container closure integrity. In
general, the addition of preservative(s), regardless of the preservative used, significantly changes the
stability profiles of proteins (Maa and Hsu, 1996; Fransson et al., 1997; Lam et al., 1997). In some
extreme cases, visible precipitation and aggregation have been reported. Therefore, the effect of
various preservatives on the stability of protein should be carefully examined. Other experiments
required to qualify a multidose formulations include the preservative effectiveness test and the stopper
self-sealing test. Detailed procedures and specification are available from the USP (U.S. Pharmacopeia),
the Ph. Eur. (European Pharmacopeia) and the JP (Japan Pharmacopeia).

Desired properties of the ideal preservative include: effectiveness at low concentration against a wide
variety of organisms; chemical stability; solubility; compatibility with the protein drug, excipients and
auxiliary agents; free from objectionable odor, taste, color and stinging; and non-toxic and non-
sensitizing both internally and externally at the required concentration. Also, it must not absorb,
penetrate, 11 or interact with containers or closures (Thompson, 1998). For further details on
preservatives, readers are referred to Regulatory Document 4 in the Appendix and Thompson (1988).
Examples of typical preservatives used for parenteral protein pharmaceuticals are benzyl alcohol,
phenol, m-cresol and benzalkonium chloride

Necessary Studies for Formulation Development

Storage Stability Study

Documenting that the formulation will keep the protein stable until the desired expiry can be the most
time-consuming part of formulation development. The expiry requirements are determined by
distribution not regulatory requirements. One year is probably too short for effective manufacturing and
distribution through normal channels. In general, a shelf life of 18 month is considered acceptable for
commercialization. Results obtained from accelerated stability studies are useful for predicting potential
degradation products and appropriate analytical methods, but whatever the actual shelf life, it must be
supported by sufficient real-time storage data to obtain regulatory approval. Thus, it is important to
establish a final formulation and start the realtime storage studies as early as possible during product
development.

Process Development.

Formulations that can be prepared on a small scale without experiencing any problems may encounter
significant problems during the scale-up of the process. For example, mixing solutions in a large stainless
steel tank, pumping solutions through stainless steel tubing, filtration and filling through a high-speed
filling machine 14 can introduce unexpected stresses to the protein. An increase in the formation of
particulates, along with a loss of proteins due to surface adsorption and aggregation, has routinely been
observed. It is important to expose the formulation to equivalent stresses and make sure that no
formulation adjustment is necessary to accommodate the manufacturing processes. Again, this testing
should be done as early in the development process as possible.

Model Predictive Performance Evaluation and Explainability

After the machine learning modeling process has been completed, it is necessary to evaluate the
predictive performance of the models. Several different metrics can be used to assess the predictive
performance, and we can divide them into regression and classification metrics. Table 3 is a summary of
the different metrics in different applications. For regression modeling tasks, coefficient of
determination (R2 ), mean squared error (MSE), root mean squared error (RMSE), and mean absolute
error (MAE) are typically used as metrics for evaluation. For classification modeling tasks, a confusion
matrix will first be applied to calculate some metrics, including accuracy, precision, recall, F1-score,
sensitivity, and specificity. However, the results from some classification metrics, such as accuracy, are
misleading in the imbalanced classification modeling task. Therefore, additional evaluation metrics such
as Receiving Operating Characteristic (ROC) area under the curve (AUC) and Cohen’s Kappa are
employed for model evaluation with an imbalanced dataset [71]. In recent years, deep learning-based
image analysis, a subfield of machine learning, has been introduced for developing solid dosage
formulations with its use in the pharmaceutical field continuing to expand rapidly [64,72]. Unlike
machine learning modeling for tabular data, deep learning-based image analysis evaluation metrics are
based on calculating pixels or voxels in the images. Therefore, other metrics such as Average Precision
(AP) and mean Average Precision (mAP) are typically used for object detection tasks [73]. Pixel accuracy,
Intersection-Over-Union, and Dice Coefficients are used for image segmentation tasks [74]

Detecting Tablet Defects

Tablet defects such as cracking, capping, binding, and sticking are common behaviors during the
manufacturing process. These defective tablets typically need to be screened out manually which
requires a massive number of laborers with the process being a challenge to scale up. To address this
problem, some techniques, such as X-ray computed tomography (XRCT), can be used to analyze the
internal structure of tablets [64,102]. To expand the application of this technique, researchers have
combined XRCT with the deep learning technique to successfully detect tablet defects [64]. Ma et al.
studied the application of convolutional neural networks in detecting internal tablet defects. In this
study, different batches of tablets containing excipients, including mannitol and microcrystalline
cellulose, were prepared and then captured by XRCT for image analysis. An image augmentation
strategy was employed, resulting in an increase of images from 573 to 43,548. A CNN containing the
following three modules was used for the image analysis: (1) UNet A, which is used to distinguish the
tablets from the bottle, (2) Module 2, which is an automated analysis used to identify individual tablets,
and (3) UNet B, which can determine internal cracks of tablets quantitatively (Figure 7). During the
model testing, The UNet neural network exhibited an accuracy of up to 94% for seven batches of tablets.
In addition, this CNN method can potentially support the detection of defects from other products and
may significantly reduce time, workload, and financial costs [64 ]
POWDER
Powders are one of the most conventional and oldest pharmaceutical dosage forms. They consist of a
dry substance composed of finely divided particles. Powders are the basis of many other dosage forms
including capsules and tablets [103]. Pharmaceutical powders can be prepared by grinding, crushing, or
comminuting, and they typically have particle sizes between 10 nm and 1000 µm [104]. AI technologies
have been successfully applied to the process control of powder engineering for both small molecules
and Figure 7. The workflow of the CNN-based deep learning method for detecting tablet cracks
(Adapted with permission [64]). 6.3. Powders Powders are one of the most conventional and oldest
pharmaceutical dosage forms. They consist of a dry substance composed of finely divided particles.
Powders are the basis of many other dosage forms including capsules and tablets [103]. Pharmaceutical
powders can be prepared by grinding, crushing, or comminuting, and they typically have particle sizes
between 10 nm and 1000 µm [104]. AI technologies have been successfully applied to the process
control of powder engineering for both small molecules and biologics. In addition, some studies have
demonstrated the great potential of AI applications in carrierbased dry powder inhalation [87,88].

Capsules

Capsules are drugs enclosed in a shell made from gelatin or other materials. Capsules are another one of
the solid dosage forms most widely used, a particularly for oral administration. However, limited
literature exists describing the application of AI methods in developing capsule-based formulations. To
obtain different drug release profiles, several types of capsules including hard gelatin, soft gelatin,
modified release, and enteric capsules have been used to encapsulate the drug powders. Zhou et al.
demonstrated the feasibility of identifying capsule defects using an enhanced CNN [92]. In this study,
capsules with different defects including holes, concave heads, uncut bodies, and oil stains, as well as
capsules that were shriveled, locked, or nested, were first prepared manually. The enhanced CNN was
equipped with L2 regularization and an Adam optimizer which were used to overcome the overfitting of
the model. In addition, K-Nearest Neighbor (KNN) and Support Vector Machines (SVM) were also
employed in this study for comparison. The results from the confusion matrix showed an accuracy of up
to 97.56% for detecting capsule defects when applying this enhanced CNN model [92].

Granules

Granules are another pharmaceutical solid dosage formulation that consists of aggregates of powder
particles with drugs and excipients. Granules offer the advantage of flexible administration for patients
who have difficulty swallowing capsules or tablets and are more shelf-stable than liquid forms. Capsules
also offer improved flowability and compressibility compared to drug bulk powder. This dosage form can
be classified into several types: modified-release granules, coated granules, effervescent granules, and
gastro-resistant granules. Wet granulation and dry granulation are the two main methods used to
prepare granules [115]. Recently, some studies have shown applications of AI tools in manufacturing
granules, in the areas of process control and the prediction of final particle size [60,94].

Solid Dispersions

As one of the most important solubilization methods for solid dosage forms, solid dispersions are
typically composed of drugs and polymers. Amorphous solid dispersion is a subfield of solid dispersion.
Amorous solid dispersion occurs when an amorphous drug is molecularly dispersed into a polymer
matrix, also known as a homogeneous drugpolymer solution [117]. A solid dispersion can be obtained by
(1) a fusion-based method such as hot-melt extrusion, and (2) a solvent-based method such as spray-
drying, and coprecipitation [118]. However, due to environmental factors such as heat, moisture,
storage time, and drug-polymer interaction, solid dispersion is physically and chemically unstable which
results in drug-polymer phase separation over time [117]. Therefore, it is crucial to consider the critical
factors including stability, miscibility, and solubility, to overcome phase separation happening during the
product development of solid dispersions. A conventional development pathway for solid dispersion
consists of the pre-formulation, formulation, and characterization stages which are time-consuming and
laborious, even though some high throughput screening methods such as solvent casting can be applied
[119]. To improve the efficiency and mitigate relatively high labor intensity during the development of
solid dispersion products, some AI-based techniques were successfully employed to predict some
characteristics including physical or chemical stability, dissolution rate, and dissolution profile of solid
dispersion formulations.

Predicting Physical or Chemical Stability

Han et al. studied the feasibility of predicting the physical stability of solid dispersion by using several
machine learning methods including ANN, SVM, RF, LightGBM, KNN, and naïve Bayes [59]. In this study,
50 drug molecules containing 646 physical stability data points were collected from the public database
for training the model. Molecular descriptors such as molecular weight, melting point, hydrogen bond
acceptor count, and heavy atom count were used as molecular representations to generate the
database. In addition, an accelerated stability study was conducted for three months and six months
under 40 ◦C/75 RH to evaluate the model’s performance in predicting its physical stability. The results
revealed that RF was the best predictive model among others, with an overall accuracy of up to 82%.
Then, a 17β-estradiol (ED)-polyvinylpyrrolidone (PVP K30) solid dispersion was prepared by solvent
evaporation for experimental validation. The validation experimental results showed that a 1:5 ratio
solid dispersion system was stable for 6-months under accelerated conditions, while a 1:2 ratio solid
dispersion system was unstable, which corresponded to the ML predictions. This is because drug loading
played an important role in physical stability by affecting the number of hydrogen bonds between the
drug and excipient and steric hindrance of the solid dispersion system [59]. In addition, chemical
stability and drug-excipient compatibility are other critical factors and must be considered during
formulation development. Wang et al. successfully developed PharmDE as an integrated platform for
drug-excipient incompatibility risk prediction by analyzing 532 data points from 228 published articles,
which potentially facilitated the initial screening of solid dispersion [120]. In conclusion, AI technologies
have been demonstrated to predict the physical and chemical stability of solid dispersion and can
potentially accelerate the product development process by shortening the stability testing time and
narrowing down the number of testing samples.

Lubrication

In general, there are four lubrication mechanisms: hydrodynamic lubrication, elastohydrodynamic

lubrication, mixed lubrication, and boundary lubrication [1,5]. As their names implies, the former three
mechanisms are related to the usage of liquid lubricants to some extent. In the pharmaceutical industry,
boundary lubrication is the most common mechanism functioning in unit operations [2]. For boundary
lubrication, a lubricant typically forms layers/film between surfaces or at interfaces to reduce friction,
where the penetration of the lubricant into surface asperities occurs. Structurally, the lubricants
commonly used for boundary lubrication are long chain molecules with active end-groups such as stearic
acid and its metallic salts. The typical end-groups include: (1) –OH (long chain alcohol); (2) –NH2 (long
chain amine); (3) –COOH (long chain fatty acids); and (4) metal ions such as Mg2+. The molecules with
these end-groups can be readily adsorbed on the surfaces of metals or other particles to form an
oriented monolayer or multilayers. The layers formed prevent further contact between the intended
surfaces and powder particles. The efficiency of a boundary lubricant is measured by the extent to which
these films can mask the field of force of the underlying surface [1]. In other words, a lubricant film such
as the film of magnesium stearate needs to be sufficiently thick to cover the surface, typically a few
layers. In addition, the breaking down of the lubricant film plays a significant role so that the motion of
lubricated surface is facilitated. This will be illustrated by our discussion on the dihydrate of magnesium
stearate, which in general gives the best lubrication efficiency due to its layered structure.

Lubrication in Pharmaceutical Processes

To prepare solid dosage forms, many pharmaceutical operations, including blending, die-filling,
compaction, capsule-filling, and compression, are utilized in the pharmaceutical industry. In these
processes, friction occurs at either powder-tool interfaces or particle-particle interfaces. For the
interaction between powder particles and the wall of equipment, it is commonly called wall friction; for
the particle-particle interaction, it is termed as internal friction. In the following sections, we focus on
the fundamental aspects of friction reduction through lubrication for both wall friction and internal
friction.

Common Lubricants Used in Drug Development

As described before, most of the lubricants used in the pharmaceutical processes are boundary
lubricants; certainly, metallic salts of fatty acids such as magnesium stearate and stearic acid are the
most Lubricants common ones. However, there are other lubricants, including fatty acid esters,
inorganic materials, and polymers, which can be used in the cases when both magnesium stearate and
stearic acid do not meet their performance expectation [13]. So, in the next section, various
pharmaceutical lubricants other than magnesium stearate and stearic acid will be briefly discussed.

Metallic Salts of Fatty Acids

Use of the metallic salts of fatty acids as lubricants has a long history in the pharmaceutical industry and
they are still the most dominant class of lubricants. Magnesium stearate, calcium stearate, and zinc
stearate are the three common metallic salts of fatty acids used and their chemical structures are shown
in Figure 3 [14]. Of these three lubricants, magnesium stearate is one of the most frequently used, and
its application will be discussed in the following sections. In this section, we concentrate on the
fundamental aspects of metallic salts of fatty acids in terms of friction reduction. Relative to fatty acids
including lauric, myristic, palmitic, and stearic acids—they are typically melted at low temperatures
(stearic acid has the highest melting point of about 69 °C), the metallic salts of fatty acids have much
higher melting temperatures: zinc stearate (120 °C), magnesium stearate (140 °C), and calcium stearate
(160 °C). In terms of the effect of chain length on friction reduction, typically friction decreases with
increasing length of the hydrocarbon chains; approximately, the coefficient of friction can be reduced
from about 0.5 to about 0.1. All in all, stearic acid has a chain length of the desired friction coefficient
reduction. In addition, temperature has little effect on lubrication until it reaches the melting points of
the lubricant. Furthermore, the structure of a lubricant layer at metal surfaces also plays a role in friction
reduction; a thick layer can maintain and sustain a friction reduction with time. However, use of too
much lubricant in tablet formulations can impact the product performance by decreasing tablet
dissolution. In summary, most of the metallic salts of fatty acids can reduce the coefficient of friction to
about 0.1. Nonetheless, other factors such as chemical compatibility will influence their use in the
pharmaceutical industry. In the following sections, we will discuss a few classes of fatty acids/salts of
fatty acids lubricants.

Fatty Acids

Fatty acids are also common lubricants used in the pharmaceutical industry with stearic acid as the most
popular one. Chemically, stearic acid is a straight-chain saturated monobasic acid found in animal fats
and in varying degrees in cotton seed, corn, and coco [14]. The commercial material of stearic acid has
other minor fatty acid constituents such as myistic acid and palmitic acid. Depending on the proportion
of various acids present, the physical structure of commercial materials of stearic acid can range from
macrocrystalline to microcrystalline. Correspondingly, its material properties can vary from hard, to
brittle, quite soft, and crumbly. For the macrocrystalline form of stearic acid, it has a ratio of stearic acid
to palmitic acid of 45:55 (w/w); for the microcrystalline form, the ratio for stearic acid to palmitic acid is
between 50:50 and 90:10. Table 1 shows the physical properties of these acids. As shown in Table 1,
stearic acid has the highest melting and boiling points of the three. In addition, the lubrication property
of stearic acid is listed in Table 2. Table 2 summarizes the friction coefficient, breakdown temperature-
transition temperature from solid to liquid-of stearic acid at various metal surfaces. As shown in Table 2,
the measured coefficient of friction varies with different metal surfaces (including steel), but their values
are close to 0.1, similar to those reported for the metallic salts of fatty acids [1]. Therefore, it is expected
that the lubrication performance of stearic acid should be similar to that of magnesium stearate at
metal surfaces.

Effect of Powder Properties on Lubrication

In practice, the effect of the hydration state of magnesium stearate on lubrication cannot be separated
from other factors such as surface areas and agglomeration [22]. The materials of magnesium stearate
obtained from various vendors or different batches of the same vendor often have varied powder
properties such as particle size, surface area, and particle shape [23]. Therefore, it is important to
understand the impact of these properties on the performance of the lubricated formulations, including
the mechanical properties of the compressed products, the dissolution of tablets, and the flowability of
powder. Generally, it is expected that the lubrication efficiency of magnesium stearate improves with
increasing its surface area or decreasing its particle size since the increase of surface area can provide
more surface coverage [24]. Consequently, with more coverage of particle surfaces by magnesium
stearate, the particle-particle bonding is weakened, resulting in weak tablets. In addition, because the
surface of API particles is covered with the lubricant which is hydrophobic, it causes slow-down of
dissolution. For instance, as reported by Dansereau and Peck [25], the tensile stress of MCC tablets
lubricated with magnesium stearate decreased with increasing surface area of the lubricant. As a result,
the friability of these tablets went up with increasing the surface area. Additionally, it was reported that
the dissolution of dexamethasone-lactose tablets was enhanced by increasing the particle size of
magnesium stearate, and the optimal size range for the lubricant was found to be from 350–500 μm
[26]. More recently, the impact of the variability of powder properties of magnesium stearate on the
roller-compacted, immediate release tablets was investigated based on a quality-by-design study [27]; in
addition to the lubricant, MCC, spray-dried lactose, and sodium starch glycolate were also included in
the study. Particularly, the effect of the variability of the lubricant on formulation performance such as
the flowability of blends, segregation propensity, hardness, and tensile strength was evaluated. It was
concluded that the ribbon tensile strength and tablet hardness significantly increased as the specific
surface area of magnesium stearate decreased (particle size increased), which is consistent with the
results reported previously.

Chemical Stability and Compatibility

Chemical instability issues of APIs in the presence of lubricants have been widely reported, especially for
magnesium stearate. Regarding the effect of magnesium stearate on the chemical instability of an API,
there are several factors to consider, including the impurities (MgO), the effect of alkalinity caused by
magnesium stearate, its catalytic effect, and other chemical reactions initiated and mediated by
magnesium ions. These will be discussed in the following sections.

Potential Interactions with Impurities (MgO)

The commercial materials of magnesium stearate contain several impurities such as magnesium oxide
(MgO) and palmitic acid; so, these impurities often react with APIs in the solid state causing stability
issues. For instance, as reported by Kararli et al., MgO reacts with ibuprofen at certain temperatures and
humidity values in the solid state [39]. Specifically, when the mixture of MgO and ibuprofen was
stressed at 40 °C and 75% RH, a significant amount of degradation was detected by differential scanning
calorimeter (DSC), thermal gravimetric analysis (TGA), and multiple internal reflectance infrared (MIR).
In fact, MgO reacted with ibuprofen to form the magnesium salt of ibuprofen. The reaction was
accelerated with increasing temperature; it degraded at 40 °C after 1 day; but at 30 °C, no significant
interaction was observed for up to 80 days. In another study, ketoprofen was found to form a eutectic
mixture with magnesium stearate [40,41]. Besides, the magnesium stearate itself also reacts with APIs,
and a few examples are given in the following passage.

Hydrolytic Degradation at Basic pH

The presence of magnesium stearate in a formulation can increase the micro-environmental pH of the
formulation, creating an alkaline condition and consequently accelerating the hydrolysis of some drugs.
For example, the degradation rate of acetylsalicylic acid (aspirin) in a blend increased with the addition
of magnesium stearate; the hydrolysis rate depended on the concentration of magnesium stearate in
the blend. This is because acetylsalicylic acid is a moisture-sensitive drug, and its degradation is often
associated with the presence of water and/or an alkaline pH condition [42–44]. In addition, Kornblum
and Zoglio [45] found that in the presence of magnesium stearate, the rate of degradation of
acetylsalicylic acid in suspensions was associated with the high solubility of the magnesium salt of
acetylsalicylic acid. Presumably, this is due to the fact that a buffer layer around the particles of
acetylsalicylic acid was formed, creating an environment that was detrimental to the chemical stability
of the compound [46]. Based on Miller and York’s [13] description, the lowering of the melting point of
acetylsalicylic acid may be facilitated by the formation of a surface film of magnesium stearate around
the particles of acetylsalicylic acid, creating intimate contact between the two materials and leading to
degradation. As a consequence of chemical incompatibility between aspirin and magnesium stearate, a
number of potentially undesirable products, such as salicylic acid, salicyl salicylic acid and acetyl salicyl
salicylic acid, are produced. Furthermore, the presence of MgO impurity in magnesium stearate may
also play a role since it could enhance the degradation by creating an alkaline pH environment. For
example, Gordon et al. noticed that in the presence of magnesium stearate, ibuprofen forms a eutectic
mixture which sublimates [47]. Additionally, quinapril (a tetrahydroisoquinoline carboxylic acid), an
angiotensin-converting enzyme (ACE) inhibitor, was also found to be incompatible with magnesium
stearate due to the basicity of the lubricant; the degradation of quinapril was mediated by the
availability of moisture.

Oxidation

The presence of magnesium stearate in a formulation can also induce an oxidation reaction. For
instance, the decomposition of drotaverine HCl was accelerated when magnesium stearate and talc
were present in a formulation [48]. In addition, the chemical instability of drotaverine hydrochloride was
significantly influenced by the pH of the formulation, and the degradation rate was largely enhanced in
the presence of magnesium stearate. Specifically, drotaverine HCl was degraded to drotaveraldine by an
oxidative degradation pathway, which can be inhibited using an antioxidant or an acidic auxiliary
material. A similar catalytic action of magnesium stearate was observed with the autoxidation of
2,6,10,14-tetramethylpentadecane, where magnesium stearate catalyzed the decomposition of
hydroperoxide first to boost autoxidation of the compound [49]. Aside from its effect on oxidation, the
metal ions from magnesium stearate also cause chemical instability.

Metal Ion-Mediated Degradation

Degradation of drugs is also mediated by the presence of magnesium ions. For example, upon an
accelerated stress treatment, fosinopril sodium was degraded into a β-ketoamide (III) and a phosphoric
acid (IV) in a prototype tablet formulation with magnesium stearate [50]. It was shown by further
investigation that the degradation of fosinopril was mediated by magnesium metal ions, and thus a
mechanism invoking metal chelation was postulated. Based on a kinetic study, it was established that
the degradation was a second-order reaction between fosinopril and magnesium. Since many drugs are
susceptible to ion-catalyzed degradation, it has been suggested that stearate salts should be avoided as
tablet lubricants. However, by addition of malic acid, hexamic acid, and maleic acid in a formulation, the
degradative effect of alkali stearates can be inhibited due to competition for the lubricant cation
between the drug and an additive acid. The incompatibility of magnesium stearate with a drug also
depends on the functional groups of the drug. For example, drugs with an amine group are often very
reactive, which is discussed in the following section.

Reaction with Amines

Many drugs contain amine groups, and amines are typically prone to reactions with excipients and salt
counter-ions. Specifically, the potential for a reaction with magnesium stearate or stearic acid is
particularly of concern when a drug has a primary amine group. In the case of norfloxacin, after a
prolonged storage at 60 °C, the formation of a stearoyl derivative was observed in the tablets containing
magnesium stearate. Other drugs, found to be incompatible with magnesium stearate, include
glimepiride, cephalexin, glipizide, ibuproxam, indomethacin, ketoprofen, moexipril, nalidixic acid,
primaquine, promethazine hydrochloride, temazepam, glibenclamide, penicillin G, oxacillin, clopidogrel
besylate and erythromycin [51]. In summary, drugs with a primary amine group are often very unstable
in formulations containing magnesium stearate. Besides the reaction associated with a primary amine
group, the incompatibility between magnesium stearate and drugs can be caused by other interactions
as well, which is described in the following section.

Other Interactions between Magnesium Stearate and Drugs

There are other interactions between drugs and magnesium stearate causing incompatibility. Captopril
(another ACE inhibitor) is a pyrrolidine carboxylic acid derivative used in the treatment of hypertension.
During grinding (5 min at room temperature at 32% or 80% RH), it was shown that captopril interacted
with a metallic stearate at surfaces, in which the mixtures of captopril and each metallic stearate gave
different results, before and after grinding, as detected by differential scanning calorimetry (DSC),
thermogravimetric analysis (TGA), and Fourier transformed infrared spectroscopy (FTIR). It appeared
that grinding accelerated the solid-state interaction of captopril with magnesium stearate. In addition,
the solid-state interaction between captopril and magnesium stearate was also evidenced by the
shifting of the IR spectral peak for the –COOH of the stearate moiety from 1578–1541 cm−1 . This can be
attributed to the interaction of the –OH group in the carboxylic acid of captopril with bridging
coordination of the –COO group of magnesium stearate via hydrogen bonding involving water; the
interaction between captopril and magnesium stearate was stopped at 60 °C due to evaporation of
water from the ground mixture.

MATERIALS AND METHODS

Materials
A total of 13 different excipients were used in this study (Table 1). The excipients studied were divided
into three groups based on their crystallinity: crystalline excipients, partially crystalline excipients,
amorphous excipients. Water Sorption-Desorption Isotherms by DVS Method The water sorption-
desorption isotherms were measured using an accurate humidity- and temperature-controlled
microbalance system, Dynamic Vapor Sorption (DVS 1, Surface Management Systems, Ltd., 3 Warple
Mews, Warple Way, London, UK). The 10–20 mg sample was predried at 258C by flowing dry nitrogen.
The relative humidity (RH) was raised in steps from 0% to 95% and back to 0%. The equilibration
condition at each step of the RH for the rate of change in mass with time (dm/dt) was selected for each
material separately. The mass changes were calculated with respect to the mass of the dried sample

Data Analysis
The experimental monolayer water values were determined from the sorption isotherms, using BET
equations15 and GAB equations16–18 for modeling the moisture sorption isotherms.

Water Sorption with the Desiccator Method

Each excipient was dried on trays at 458C and 70– 75 mbar for 24–48 h in a vacutherm (Heraeus VT
6025, Kendro Laboratory Products GmbH, 63450 Hanau, Germany) and then dried further at 228C in the
vacuum desiccator (Nalgene desiccator, Nalge Company, Rochester, NY) at RHs of 0% for 5 days. The
moisture sorption properties of the excipients (500 mg/sample) were determined gravimetrically before
and after storage at 228C under conditions of differing RH (0%–95% RH). The various RH conditions were
achieved in vacuum desiccators using saturated salt solutions. The relative humidities were 0% RH (silica
gel), 11% RH (lithium chloride), 23% RH (potassium acetate), 33% RH (magnesium nitrate), 43% RH
(potassium carbonate), 52% RH (magnesium nitrate), 59% RH (sodium bromide), 75% RH (sodium
chloride), 85% RH (potassium chloride), 95% RH (disodium hydrogen phosphate), and all the salts were
of reagent grade. Samples in triplicate in open glass vials were allowed to equilibrate in the vacuum
desiccator and were stored for 2 weeks.

X-Ray Powder Diffractometry (XRPD)

The X-ray diffraction patterns were measured as previously described.10 The sorption samples were
measured at room temperature after a 2- week storage under conditions of differing RH (0%–95% RH) in
the desiccators. The thermal processing samples were measured using a variable-temperature X-ray
powder diffraction (VT-XRPD) theta–theta diffractometer (Bruker axs D8, Bruker AXC GmbH, Karlsruhe,
Germany). Both dry and wet masses at different water contents for each excipient (Table 1 and Fig. 5)
were placed into the holder of an XRPD. The wet masses were performed with a mortar and pestle to
simulate the early stages of preformulation. Each sample was heated at increments of 108C from 258C
to 1808C–2708C (depending on the melting temperature) and maintained at the target temperature for
15 min. The heating rate was 0.28C/s, angular range was 58–408, with increments of 0.18, and the
measuring time was 1 s/ step (38 (2y)/min). The variable-temperature diffraction patterns of the wet
masses were measured 24 h after addition of water to ensure a uniform distribution of water. This
method enabled us to follow the phase transformations of each excipient during the thermal processing.
Estimation of the crystallinity was calculated as previously described.1

Near Infrared Spectroscopy

Offline near-infrared (NIR) spectra were measured as previously described.10 The sorption samples
were measured at room temperature after a 2-week storage under conditions of differing RH (0%–95%
RH).

Specific Surface Area

The specific surface area was measured using the nitrogen-adsorption technique based on the BET
theory (TriStar 3000, Micromeritics, Inc., Norcross, GA). The samples were outgassed under vacuum at
408C for 1200 min. The specific surface area was calculated based on three points of the relative
pressure 0.1, 0.2, and 0.3 in accordance with the current United States Pharmacopoeia (USP) version.
The acceptance criteria for the correlation coefficient was at least 0.9975. The masses of the samples
were calculated by weighing first the empty sample tube and stopper assembly and the tube with the
dried sample plugged by the stopper after drying before analysis.

Particle Size Distribution

The volume particle size distribution was determined using a method based on laser light diffraction
(Laser Diffraction Particle Size Analyzer LS13 320, Beckman Coulter, Inc., Miami, FL). The samples were
measured using air as the medium and were prepared by dispersing powder in the unique Tornado Dry
Powder System.

PHARMACEUTICAL PREFORMULATION AND ITS SIGNIFICANCE IN THE DEVELOPMENT

OF SOLID DOSAGE FORMS
The manufacturing of standard tablets requires extensive knowledge of the physicochemical properties
of a drug substance/API molecule. Preformulation parameters, which determine the final dosage form
and the development plan, are important. Preformulation is a stage where the physicochemical
properties of the drug substance and the suitable pharmaceutical excipients are characterized. The
objective of the preformulation is to choose the correct drug molecule with the correct ingredients.
Preformulation also indicates the compatibility and understanding of the drug stability characteristics.
Evaluation parameters are commonly used in the preformulation of drug development; these include
solid-state properties, solubility, and stability. Drug stability, safety, content uniformity, and in vitro
dissolution rates can be significantly influenced (Hickey and Smyth, 2011). Preformulation studies begin
with the evaluation of the drug substance purity, which plays a more significant role. The purity and
homogeneity of the drug substance is essential for the efficacy and safety of the pharmaceutical
product. Impurities can be a result of the starting materials, synthetic intermediates, the manufacturing
process or degradation products (Impurities in New Drug Substances, n.d.; RaoNageswara and Nagaraju,
2003; Grekas, 2005; Guy, 2000). Various analytical techniques are used to determine the purity of drug
substances, such as differential and gravimetric thermal analysis, high-performance liquid
chromatography (HPLC) and thin-layer chromatography (TLC). Organoleptic properties such as color,
odor, and taste are recorded for the new drug substance. If the color is undesirable, the incorporation of
a dye is recommended to improve appearance of the final product. If the drug has an undesirable odor
or taste, it is recommended that a suitable salt form of that drug is made. Many drug substances exist in
a crystalline form (Mortko et al., 2010; Wischke et al., 2010). A crystalline particle is characterized by a
definite crystal habit that relates to the external structure (such as shape and size) and a crystal lattice
that describes the internal structures. A change in the crystal form (polymorph) has a significant effect
on the drug particles’ mechanical properties such as particle strength, flowability, miscibility, and tablet
dissolution rate and stability. Therefore, to avoid polymorphic transformation of the pharmaceutical
powder during preformulation, it is important to identify any potential change in the internal and
external structures of the pharmaceutical material. Various instrumental techniques are used for
investigation of the solid state.

SOLUBILITY
The solubility of a drug is an important preformulation property as it significantly affects the
bioavailability of the drug. USP and BP classify the solubility in terms of the solvent required to solubilize
1 g of the drug at a specified temperature (Fig. 1). The solubility of the drug is usually determined by the
kinetic solubility and the equilibrium solubility.

pKa
The majority of drugs are weakly acidic or basic. Therefore based on the pH value, drugs will exist as
either an ionized or an unionized species. However, unionized drug molecules are more lipid soluble and
therefore will be absorbed more effectively than ionized drug molecules. The Henderson-Hasselbach
equation provides an estimate of the ionization of a weak acid or base at a given pH.

For acidic drugs

pH = pKa + log [ ionized form ] / [ un-ionized form ]

For basic drugs

pH = pKa + log [ un- ionized form ] / [ ionized form ]

The pKa of a drug can be determined by using UV or visible spectroscopy, potentiometric titration,
conductimetry, or dissolution rate method.

Partition coefficient (log P)

Partition coefficient (oil/ water) is an indicator of drug lipophilicity. The partition coefficient is
determined by the shake flask method using two immiscible solvents, the most common hydrophilic
solvent is water or phosphate buffer of pH 7.4, and for oil phase is octanol.

The partition coefficient is defined as the ratio of unionized drug distributed between the
organic phase (Corganic) and aqueous phases (Caqueous ) at equilibrium.
As the Ko/w value increases, the drug’s ability to cross the biological cell membrane increases.
The concentration of a compound in each phase is determined by HPLC. Since biological
membranes are lipid centric, a highly lipophilic drug molecule exhibits passive absorption.
However, it may have issues with low solubility. Therefore, an optimal balance between these
two opposing properties is highly desirable for drug absorption.

STABILITY STUDIES
The primary objective of stability testing is to provide various inputs for drug product development such
as pharmaceutical processing, storage, and drug absorption at gastrointestinal mucosa. A
preformulation stability study mainly comprises solid state, solution phase stability, physical stability,
and photostability studies (Fig. 4). Solid-state stability testing is performed for solid dosage forms where
the drug and excipient samples are exposed to extreme temperatures and humidity. Solid-state stability
studies also provide information on possible routes of degradation, and degradation products of the
drug substance. Various qualitative and quantitative analytical tools are used to detect drug
degradation. A well-developed and validated stability method can be used in the latter stages, such as
stability testing for clinical studies and stability testing for product license applications. Solution-phase
stability studies provide information on the stability of a drug in granulating solvent and in
gastrointestinal fluids. These studies include the degradation studies in 0.1 N HCl, 0.1 N NaOH, and
water at 90°C, effect of pH, and oxidation studies. The application of appropriate testing will provide
important information to formulation scientists on various factors that will affect product stability,
potential compatible excipients, and preferred storage conditions.

DRUG-EXCIPIENT COMPATIBILITY STUDIES

Studies of possible drug-excipient interactions are an important phase in preformulation development.
Commonly used excipients in solid dosage forms are binders, fillers, disintegrants glidants, lubricants,
and diluents. The potential physical or chemical interactions between drug and excipient may affect the
chemical nature, therapeutic activity, and stability of the dosage form (Bharate et al., 2010). Therefore,
knowledge of possible drug-excipient interactions is important in selecting the suitable excipient. There
is adequate information available on known drugs. However, in compatibility studies for new drugs or
excipients, the preformulation scientist must produce the required compatibility data. The desired ratio
of drug to excipient used in drugexcipient compatibility studies is usually 1:1, but can be subject to the
ratio required in the final formulation. Required ratios of drug to excipient are kept in glass vials and
then subjected to 50°C and 80% RH for the duration of 1 month (Budura et al., 2011). The analytical
techniques used for studying the physical and chemical properties of possible drug-excipient
interactions include: thermal analysis (DSC, DTA), spectroscopic methods (X-ray diffraction, FT-IR, NMR),
and chromatographic methods (HPLC, LC-MS) (Rus et al., 2012; Gibson, 2009). Compatibility studies
between drug and excipient will provide information on the efficacy, safety, and stability of the drug
product.

DILUENTS
Diluents are used to increase the size of the dosage form. Diluents are usually added to tablets where
the active constituent is in low dose and to improve the powder flow and compaction properties prior to
direct compression. Diluents are commonly used in the range between 5% and 80%. A good filler should
be chemically inert, nonhy-groscopic, have good flow and compaction properties, be water soluble, have
pleasant taste, and be cost effective. Commonly used diluents are lactose, microcrystalline cellulose-
Avicel (PH 101 and PH 102), calcium phosphate, starch. Lactose is used in hydrous and anhydrous forms:
anhydrous lactose is used in direct compression and lactose monohydrate is used in wet granulation
process. Although lactose is an inert filler, it is unsuitable for people with lactose intolerance.
Microcrystalline cellulose is highly compressible and more extensively used for direct compression. It
also exhibits disintegrant activity and binder activity. Calcium phosphate is used both as wet granulation
and direct compression. However, it was observed that it interferes bioavailability of tetracycline tablet.

DISINTEGRATING AGENTS
Disintegrating agents are considered important excipients, which facilitate the breaking of the dosage
form when it comes in contact with GI (gastrointestinal) fluid. The disintegrating agent assists the onset
of dissolution and subsequently provides for faster drug absorption. Disintegrants are classified into
disintegrants (microcrystalline cellulose, colloidal silicon dioxide, alginate, and starch), and
superdisintegrants (crospovidone sodium, starch glycolate, and croscarmellose sodium).
Superdisintegrants have recently been developed to improve the disintegration processes and result in
tablets, which swell up faster at relatively low concentrations and possess superior powder compression
properties than normal disintegrants. Disintegrants can be added by three methods: intragranular
(before granule formation), extragranular (before the tablet compression), and both (intragranular and
extragranular addition). Swelling, porosity, capillary action (wicking), and deformation have been the
main observed mechanisms of disintegration (Bele and Derle, 2012). Factors that can affect
performance of disintegrants include particle size, compression force, method of addition, and moisture
content. In addition, it has been shown that performance of disintegrants can be altered significantly
when mixed with various excipients. Excipients can influence disintegration due to the amount of
hydrophobic lubricant, the quantity of binder, and hydrophobic coating. Hence, care must be taken to
optimize the formulation. Generally, disintegrants are hygroscopic in nature and if it absorbs moisture
from the air there is a potential to impair the stability of the formulation. Thus, for moistur be provided.

COATING MATERIALS
Tablet coating is the process where coating material is applied to the surface of the tablet to achieve the
desired properties of dosage form over the uncoated variety. The advantages of coating are listed
below.

• Improving taste, odor, and color of the drug

• Improving ease of swallowing by the patient

• Improving product stability

• To protect against the gastric environment

• To improve mechanical resistance of the dosage form

• Modifying release properties

Sugar coating
Unlike film coating, sugar coating is a more laborious multistep process, leading to final tablet weight
increases of up to 30%–50%, significantly increasing tablet size. The process of sugar coating involves
various steps, i.e., sealing, subcoating, smoothing, coloring, and polishing.

Sealing
A seal coat is applied over the tablet core to protect against water penetration into the tablet from the
sucrose coatings to follow. Hence, it offers good stability of product and can also strengthen the tablet
core. Sealing coat consists of Shellac, cellulose acetate phthalate (CAP), polyvinylacetate phthalate
(PVAP), hyroxylpropyl cellulose, hyroxypropyl methylcellulose (HPMC), and Zein (a corn protein
derivative) Shellac was previously used as a sealant. However, this has largely been replaced by zein CAP
and PVAP due to polymerization problems. The amount of sealing coat material depends on tablet
porosity and batch size; hence, optimizing the quantity of sealing coating applied is very important to
ensure tablet cores are sealed effectively.

Subcoating
Subcoating is performed to round the tablets edges. In this process, there is a significant increase in
tablet weight. Generally, lamination process and suspension process methods are used for subcoating.
In lamination process, the subcoat mixture consists of sucrose and binder solution such as acacia or
gelatin, which is applied over the tablet surface followed by powder containing materials such as
calcium carbonate, titanium dioxide, calcium sulfate, and talc. Finally, drying air is applied in order to
evaporate the water. During the suspension process, a suspension of fillers in gum solution is applied.
After that, sucrose solution is applied followed by drying. Suspension process is suitable for automatic
methods.
Smoothing
Smoothing process is applied in order to smooth out subcoated rough surfaces and to increase tablet
bulk to desired size. Smoothing syrup generally consists of 60%–70% sugar solid. In some cases,
however, syrup also comprises acacia, gelatin, pigments, starch, or opacifier. Smoothing is performed
many times (about 10 cycles), until tablets are suitable for the next (coloring) phase.

Coloring
Coloring phase is a significant step in sugar-coating process, which gives the tablet improved
appearance and stability. Sugar-coating solution consists of 70% syrup and other coloring pigments.
Previously water-soluble dyes (coloring agents) were mainly used as for sugar-coated tablets. However,
water-soluble dyes are generally associated with color migration problems, and dyes usually transfer to
the surface of the tablets during drying. Hence, the use of water-insoluble pigment (lakes) has now
replaced the dyes, which provides even tablet color and maintains batch-to-batch color uniformity.

MANUFACTURING METHODS FOR ORAL SOLID DOSAGE FORM

Tablet formulation methods can be divided into two groups, direct compression and granulation. There
are a number of other novel granulation methods available to pharmaceutical manufacturers, but these
are used less frequently, i.e., pneumatic dry granulation (PDG), melt granulation, foam granulation,
moisture-activated dry granulation (MADG), spray-drying granulation, extrusion granulation. Choosing
the optimum formulation method is important because the final tablet performance will be dependent
on method of tablet manufacturing. Hence, the process selection is based on thorough knowledge of
chemical properties of the drug and excipients, their compatibility in the formulation, its ability to flow,
and finally its release properties. API characteristics, such as the melting point, moisture/temperature
sensitivity, flowability and compressibility/compactability, are critical parameters in determination of a
suitable formulation method. API characteristics and their preferred tablet formulation methods are
given in Table 6. In the pharmaceutical industry, selection of a particular manufacturing method is often
based on individual experience; for instance, for any given API compound, different industries can have
very different approach. This section will focus on the importance of granulation in the production of
oral dosage forms and the main advantages and disadvantages of each technique. Oral solid dosage
forms unit operations are determined according to which manufacturing techniques been applied. This
includes: feeding, blending, milling granulation, drying, compression/encapsulation, and coating. A
typical primary unit operation matrix in oral solid dosage form is shown in the schematic flowchart (Fig.
5). In Section 5, detailed reviews on all key unit operations associated with tablet manufacturing process
are discussed. This is a broad topic; therefore, the process described here simplifies processing of the
formulations, and those interested in studying the subject area further are encouraged to refer
additional text for supplementary details and texts listed in the reference section.
CONCLUSIONS
Oral solid dosage medicines remain the most widely used medicinal forms. The development of an oral
solid dosage drug begins with the physicochemical properties of the API molecule, involves rigorous
preformulation assessments to characterize the needs of the API, requires selection of appropriate
processing routes to handle and deliver the required specification, and continues to evolve with
technology and analytical advances. An insight into each aspect of oral solid dosage development has
been presented here to assist the reader in understanding the complexities and challenges involved in
producing these valuable medicinal form.

we have highlighted how AI tools can be harnessed for developing solid dosage formulations and how
they can be utilized in different formulations. Though most studies have demonstrated that AI can
revolutionize the drug discovery pipeline, AI has also shown more and more potential in formulation
development. Compared to the conventional formulation development pathway which uses the trial-
and-error method and requires a laborious workload, an AI-based development strategy tends to
expedite the development process by allowing scientists to generate low-cost predictions in a relatively
rapid manner. This review also discussed multiple AI algorithms used for various tasks and provided
general guidance for model selection to better help scientists to integrate AI techniques into their
research. In addition, we introduced data processing and model evaluation strategies to provide a tool
for systematically understanding and implementing AI models. More importantly, we categorized
different pharmaceutical formulations and summarized their available AI prediction models in the
published literature

REFERENCE

 Chang, B.S. and Hershenson, S. 2002. Practical approaches to protein formulation development.
in "Rationale Design of stable protein formulations-theory and practice" (J.F. Carpenter and M.C.
Manning eds.) Kluwer Academic/Plenum publishers, New York, pp. 1-25
 Division of Molecular Pharmaceutics and Drug Delivery, College of Pharmacy, The University of
Texas at Austin, Austin, TX 78712, USA
 Drug Product Science & Technology, Bristol-Myers Squibb Corporation, 1 Squibb Dr., New
Brunswick, NJ 08903, USA;
 1 Pharmaceutical Technology Division, Faculty of Pharmacy, University of Helsinki, Finland
2 Orion Pharma, Orionintie 1, Espoo, Finland
3 Viikki Drug Discovery Technology Center (DDTC), University of Helsinki, Finland
 Patel, H., Shah, V., & Upadhyay, U. (2011). New pharmaceutical excipients in solid dosage
forms-A review. International Journal of Pharmacy & Life Sciences, 2(8).