“POOR WATER SOLUBILITY AND FORMULATION OPTIONS FOR

POORLY WATER-SOLUBLE DRUGS”

TOPIC REVIEW ASSIGNMENT

LECTURER: PANNA THAPA, B. PHARM, M. PHARM, PHD

BY

BIBEK SHRESTHA

DEPARTMENT OF PHARMACY

SCHOOL OF SCIENCE

KATHMANDU UNIVERSITY

DHULIKHEL, NEPAL

SUBMITTED ON 6th OCTOBER, 2021

 Table of Contents Page

1. Introduction ................................................................................................................................................. 1

2. BCS and solubility ....................................................................................................................................... 1

3. Factors affecting Solubility ......................................................................................................................... 3

3.1. Particle size .............................................................................................................................................. 3

3.2. Pressure .................................................................................................................................................... 3

3.3. Temperature ............................................................................................................................................ 3

3.4. Molecular size .......................................................................................................................................... 3

3.5. Nature of the solute and solvent ............................................................................................................. 3

3.6. Polymorphs .............................................................................................................................................. 4

4. Importance of solubility enhancement ...................................................................................................... 4

5. Technologies of solubility enhancement .................................................................................................... 5

5.1. Particle size reduction ............................................................................................................................. 5

5.1.1. Micronization............................................................................................................................... 5

5.1.2. Nanosuspension ........................................................................................................................... 6

5.1.3. Sonocrystallization ...................................................................................................................... 6

5.2. Solid dispersion........................................................................................................................................ 6

5.2.1. Hot melt method .......................................................................................................................... 7

5.2.2. Solvent evaporation method ....................................................................................................... 7

5.2.3. Hot-melt extrusion....................................................................................................................... 7

5.2.4. Melting-solvent method .............................................................................................................. 8

 5.3. Supercritical fluid (SCF) process ........................................................................................................... 8

5.4. Cryogenic techniques .............................................................................................................................. 8

5.5. Inclusion complex formation-based techniques.................................................................................... 9

5.6. Micellar solubilization............................................................................................................................. 9

5.7. Hydrotrophy .......................................................................................................................................... 10

5.8. Crystal engineering ............................................................................................................................... 10

5.9. Chemical modification .......................................................................................................................... 11

6. Developability Classification System (DCS) .......................................................................................... 11

Reference .......................................................................................................................................................... 14
1. Introduction

Advances in science and technology have resulted in the emergence of thousands of

possible therapeutic candidates, one of which is poor water-soluble drugs. Because of the

poor solubility, pharmaceutical researchers are unable to generate economically viable and

effective formulations. 70-80% small molecules for new drug development candidates are

poorly water soluble. In vitro formulation challenges resulting from poor solubility include

limited delivery technology options, a complicated dissolution testing technique, and a poor

connection to in vivo absorption. These problems frequently cause the development of

novel drugs to be halted. The process of a medicine from discovery to marketing approval

is lengthy and expensive, costing around $1 billion. [1]

The process of a drug from discovery to marketing approval is lengthy and expensive,

costing around $1 billion. Despite the fact that only five out of every 5,000 potential drugss

are examined in clinical trials, and only one of these will be authorized for usage in patients.

When a compound with low water solubility reaches the market, it is likely to perform

poorly due to low levels of absorption. [1]

2. BCS and solubility

The introduction of the biopharmaceutics classification system (BCS) in the 1990s had a

significant impact on the development of immediate release (IR) oral dosage forms,

allowing bioequivalence of low risk (BCS class I) compounds to be established using in

vitro data rather than in vivo human studies. [2,3]

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According to the Biopharmaceutical Classification System (BCS), drug substances are

classified on the basis of their solubility and permeability.

Class I – high permeability, high solubility

Class II – high permeability, low solubility

Class III – low permeability, high solubility

Class IV – low permeability, low solubility

Thus, majority of the poorly water-soluble drugs belongs to BCS class II or class IV. This

classification system defines the boundaries for drug substances, which can be summarised

as:

a) Rapidly Dissolving – 85% of label amount of drug dissolves within 30 min in vitro.

b) Highly Soluble – highest dose strength soluble in 250 ml water at pH range 1-7.5

c) Highly Permeable – absorption in humans 90% of an administered dose.

In the physiological pH range, the BCS utilizes a definition of solubility based on the lowest

solubility in 250mL. Because many drugs have pH dependent solubility, and even if a drug

has pH independent solubility in the physiologically relevant range, solubilisers present in

the gut from gastro-intestinal secretions and food intake contribute to drug solubilization,

this is likely an underestimate of the actual solubility experienced in vivo. [4]

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3. Factors affecting Solubility

3.1. Particle size

The surface area to volume ratio increases as the particle size decreases, and the bigger

surface area allows for more contact with the solvent. As a result, the smaller the particle

size, the larger the dissolving and, as a result, the higher the solubility. [5]

3.2. Pressure

The solubility of gaseous solute increases with the increase in pressure. In case of solid

and liquid solutes, decrease in pressure has practically no effect on the solubility.[6]

3.3. Temperature

Temperature has a significant impact on solubility. In an endothermic process,

solubility increases as temperature rises, for example, the solubility of potassium nitrate

rises as temperature rises, but in an exothermic process, solubility decreases as

temperature rises. The solubility of calcium oxide, for example, reduces as the

temperature rises. The solubility of gaseous solutes diminishes as the temperature of the

solution rises. [5]

3.4. Molecular size

The solubility of a drug is determined by its molecule size; the larger the molecule, the

lower the solubility; this is because larger molecules are more difficult to surround with

solvent molecules in order to solvate the material. [5]

3.5. Nature of the solute and solvent

A solute's solubility in a solvent is solely determined by the polarity of the solute and

solvent molecules. Non-polar solutes, in general, dissolve in non-polar solvents and

3
 vice versa. The molecule of polar solutes has a positive and negative end. If the solvent

molecule is also polar, the solvent molecules' positive ends will attract the solute

molecules' negative ends. The interaction between dipoles is known as dipole-dipole

interaction.

3.6. Polymorphs

The crystal is a regular geometric arrangement or lattice made up of atoms, ions, and

molecules that is constantly repeated in three dimensions. Polymorphism refers to a

substance's ability to crystallize in several crystalline forms. All crystals have the ability

to crystallize in a variety of polymorphic forms. The melting point of these polymorphs

might vary. The polymorphs will have varied solubilities since the melting point of the

solid is connected to its solubility. Because of the minor changes in free energy, the

range of solubility differences in polymorphs is only approximately 2-3 times. [7]

4. Importance of solubility enhancement

Because of its convenience of administration, high patient compliance, cost-effectiveness,

sterility limitations, and flexibility in dosage form design, oral ingestion is the most

convenient and widely used mode of drug delivery. As a result, many generic drugs

manufacturers are more likely to develop bioequivalent oral drug products. [8] The poor

bioavailability of oral dose forms, on the other hand, is a major difficulty in their design.

Aqueous solubility, drug permeability, dissolution rate, first-pass metabolism, pre-systemic

metabolism, and sensitivity to efflux mechanisms all affect oral bioavailability. Poor

solubility and permeability are the two most common causes of low oral bioavailability.

Solubility is also important in other dosage forms, such as parenteral formulations. One of

the most critical characteristics for attaining the optimum drugs concentration in systemic
4
 circulation and producing the desired pharmacological response is solubility. Drugs that are

poorly water soluble require substantial dosages to achieve therapeutic plasma

concentrations following oral administration. Any medicine that needs to be absorbed must

be in the form of an aqueous solution at the absorption site. For liquid medicinal

formulations, water is the preferred solvent. [9,10]

One of the most difficult components of the drug development process, particularly for

oral-drug delivery systems, is improving drug solubility and thus oral bioavailability. There

are a variety of methods for improving the solubility of poorly water-soluble

pharmaceuticals that have been documented in the literature. The methodologies are chosen

based on factors such as the qualities of the drug in question, the nature of the excipients to

be chosen, and the nature of the intended dosage form.

Insufficient bioavailability is frequently caused by the poor solubility and low dissolution

rate of weakly water-soluble drugs in aqueous gastrointestinal fluids. Bioavailability can be

improved by enhancing the drug's solubility and dissolution rate in gastrointestinal fluids,

especially for class II (low solubility and high permeability) compounds, according to the

BCS. Because drug release and solubility in the stomach fluid, is the rate limiting step for

BCS class II drugs rather than absorption. i.e., boosting solubility increases bioavailability.

[8,11,12]

5. Technologies of solubility enhancement

5.1. Particle size reduction

5.1.1. Micronization

Another common process for particle size reduction is Micronization. Micronization

enhances the rate of drug dissolution by increasing the surface area of the drug, but it
5
 does not increase equilibrium solubility. The rate of dissolution of these

pharmaceuticals is improved by reducing the particle size of these drugs, which results

in an increase in surface area. Drugs are micronized utilizing milling processes such as

jet mills, rotor stator colloid mills, and so on. Because micronization does not modify

the drug's saturation solubility, it is not ideal for drugs with a high dose number.[12]

5.1.2. Nanosuspension

Nanosuspensions are the colloidal dispersion of drug particles stabilized by surfactants.

Because of their higher surface area, they have a faster disintegration rate. Tarazepide,

atovaquone, amphotericin B, paclitaxel, and bupravaquone have all been developed

using this method. The conversion of a high-energy polymorph into a low-energy

crystalline form, which may or may not be therapeutically active, is the most important

factor impacting particle size reduction. [13,14]

5.1.3. Sonocrystallization

This method is based on ultrasound-assisted crystallization. In order to induce

crystallization, sonocrystallisation uses ultrasound power with a frequency range of 20–

100 kHz. This approach improves nucleation rates, reduces size, and regulates the size

distribution of active pharmaceutical components (API).[15]

5.2. Solid dispersion

Solid dispersion is a phrase used to describe a collection of solid products made up of

at least two separate components, usually a hydrophilic matrix and a hydrophobic drug.

Polyvinylpyrrolidone (Povidone, PVP), polyethylene glycols (PEGs), and Plasdone-

S630 are the most often utilized hydrophilic carriers for solid dispersions. Surfactants

such as Tween-80, docusate sodium, Myrj-52, Pluronic-F68, and sodium lauryl

6
 sulphate (SLS) are also used in solid dispersion formulation.[16] Following are the

methods used for preparation of solid dispersions:

5.2.1. Hot melt method

The main prerequisite for this approach is that the Drug and carrier are miscible in

molten form. The thermostability of both the drug and the carrier is another important

consideration. The presence of a miscibility gap in the phase diagram results in a non-

molecularly dispersed product.

5.2.2. Solvent evaporation method

Solid solutions are made by dissolving the drug and carrier in a common solvent and

evaporating the solvent under vacuum in this procedure. It is critical that both the drug

and the carrier are soluble enough in the solvent. The disadvantage of this technology

is that it demonstrates the solvent's detrimental impact on the environment and leads to

greater manufacturing costs due to the additional facility required for solvent cleanup.

The hot melt extrusion method is typically selected due to the hazardous nature of the

organic solvents utilized in this procedure. [17,18]

5.2.3. Hot-melt extrusion

Hot-melt extrusion is similar to fusion with the exception that the extruder causes

intensive mixing of the components. Miscibility of the drugs with the matrix, just like

in the traditional fusion procedure, could be an issue. For heat-sensitive materials, large

shear forces resulting in a high local temperature in the extruder are an issue. In

comparison to the classic fusion approach, however, this technology allows for

continuous production, making it appropriate for large-scale production. Furthermore,

7
 the product is easier to handle because the shape can be modified to the next processing

stage without grinding at the extruder's outlet.[18]

5.2.4. Melting-solvent method

The drugs is dissolved in a liquid solvent and then mixed into a PEG melt that can be

obtained at temperatures below 700°C. The selected solvent and the dissolved drugs do

not have to be miscible with the PEG melt. The polymorphic form of drug precipitated

in the solid dispersion can be affected by the liquid solvent utilized in the investigation.

5.3. Supercritical fluid (SCF) process

Supercritical fluids are fluids whose temperature and pressure are greater than its

critical temperature (Tc) and critical pressure (Tp), allowing it to assume the properties

of both a liquid and a gas. SCFs are highly compressible at near-critical temperatures,

allowing small changes in pressure to dramatically affect the density and mass transport

characteristics of the fluid, which define its solvent power. The drug particles can be

recrystallized at much smaller particle sizes after being solubilized in the SCF (typically

carbon dioxide). SCF methods allow drugs particles to be micronized within limited

particle size ranges, typically to submicron levels, thanks to their flexibility and

precision. [19,20]

5.4. Cryogenic techniques

Cryogenic techniques have been developed to increase the pace of drug dissolution by

producing nanostructured amorphous drug particles with a high degree of porosity at

extremely low temperatures. The type of injection device (capillary, rotary, pneumatic,

and ultrasonic nozzle), nozzle location (above or below the liquid level), and cryogenic

liquid composition can all be used to characterize cryogenic inventions

8
 (hydrofluoroalkanes, N2, Ar,O2, and organic solvents). [21,22,23] Dry powder can be

obtained after cryogenic processing using a variety of drying methods such as spray

freeze drying, atmospheric freeze drying, vacuum freeze drying, and lyophilization.

Some of these techniques are:

• Spray Freezing onto Cryogenic Fluids

• Spray Freezing into Cryogenic Liquids (SFL)

• Spray Freezing into Vapor over Liquid (SFV/L)

• Ultra-Rapid Freezing (URF)

5.5. Inclusion complex formation-based techniques

Inclusion complexes are produced when a nonpolar molecule or a nonpolar section of

a molecule (referred to as a guest) is inserted into the cavity of another molecule or

group of molecules (known as host). Cyclodextrins are the most prevalent host

molecules. Cyclodextrins are cyclic oligomers formed by the enzymatic breakdown of

starch by cyclodextrin-glycosyltransferase (CGT) (CDs). These oligosaccharides are

nonreducing, crystalline, water soluble, and cyclic, with glucose monomers organized

in a donut-shaped ring with a hydrophobic cavity and a hydrophilic outer surface. The

hydrophobic cavity offers a habitat for correctly sized non-polar molecules, while the

surface of the cyclodextrin molecules makes them water soluble. It can create a 1: 1 or

1: 2 drug cyclodextrin complex depending on the structure and characteristics of the

drug molecule. [24]

5.6. Micellar solubilization

Surfactants are arguably the most basic and oldest approach for improving the

dissolving performance of poorly soluble medicinal compounds. Surfactants lower

9
 surface tension and promote lipophilic drug solubility in aqueous media. They're also

utilized to keep drug suspensions stable. Micelle production happens when the

concentration of surfactants surpasses their critical micelle concentration (CMC),

trapping the drugs within the micelles. Micellization is a process that improves the

solubility of drugss that aren't very soluble. Surfactant also promotes solid wetting and

increases the pace at which solids disintegrate into finer particles. Commonly used

surfactants are polysorbates, polyoxyethylated castor oil, lauryl macro glycerides etc.

[9]

5.7. Hydrotrophy

Hydrotrophy is a solubilization process in which the hydrotropic agents increase the

water solubility of the first solute by adding a substantial amount of second solute. Ionic

organic salts, also known as hydrotropic agents, are made up of alkali metal salts of

different organic acids. The term "hydrotrophy" refers to the increase in water solubility

caused by the presence of a substantial number of additives. The method by which it

improves solubility is more closely linked to complexation, which involves a weak

contact between hydrotropic agents such as sodium benzoate, sodium acetate, sodium

alginate, and urea and poorly soluble drugs. [25,26]

5.8. Crystal engineering

For the regulated crystallization of drugs, crystal engineering techniques are being

developed to generate high purity powders with well-defined particle size distribution,

crystal habit, crystal shape (crystalline or amorphous), surface nature, and surface

energy. It is possible to generate crystals with varied packing arrangements by changing

the crystallization circumstances (using other solvents, changing the stirring, or adding

10
 other components to the crystallizing drug solution). These crystals are known as

polymorphs. As a result, physicochemical parameters such as solubility, dissolving rate,

melting point, and stability may differ between polymorphs of the same drugs. Most

drugss have structural polymorphism, thus it's best to produce the drug's most

thermodynamically stable polymorph to ensure consistent bioavailability during its

shelf life in a variety of real-world storage settings. [12,27,28]

5.9. Chemical modification

Increasing the solubility of ionizable organic solutes by changing the pH is an alternate

strategy. The solubility of a solution can be increased exponentially by altering the pH.

This method can be used with drugs or substances that are weak acid (low pKa) or weak

basic (low pKa) (high pKa). Changes in the pH of the solvent are ineffective in

improving the solubility of hydrophobic and non-ionizable compounds; instead,

changes in the solvent's dielectric constant or the addition of co-solvents can improve

the solubility to a larger extent. Salt production is another useful way for improving the

solubility and dissolving rates of acidic and basic drugs.[29,30] An alkaloid base, for

example, is mildly soluble in water, but when acid is added, the pH of the medium is

decreased and the solubility of the base increases. Because the base is transformed to

salt, which is relatively soluble in water, this occurs. Similarly, salt production can

improve the solubility of a somewhat soluble acid if the pH is raised by adding alkali.

6. Developability Classification System (DCS) [4]

It is a revised version of BCS designed to accurately categorize drugs according to factors

limiting their oral absorption. It incorporates following concepts:

11
• An estimate of human fasting intestine solubility (e.g., using FaSSIF) as the major

measure of in vivo solubility that can be used to forecast the extent of human

absorption. Single values for solubility and permeability in the upper small intestine

are believed to properly represent solubility and permeability in the oral absorption

region. A fluid volume of roughly 500mL is a good estimate of the total volume of

fluid accessible in the GI tract for drug breakdown in the fasting state.

• The solubility limited absorbable dose (SLAD) hypothesis is based on the premise

that permeability and solubility, at least for class II medicines, are compensatory.

The barrier between class IIa and IIb for high permeability medications, and the

boundary between class III and IV for low permeability pharmaceuticals, represents

the solubility limiting absorbable dose. It can be written as:

Where

Ssi is the estimate of small intestine solubility,

V the fluid volume (500mL) and

Mp is the permeability dependent multiplier. For a high permeability drug, Mp is

equal to the absorption number (An), but it is kept at unity for low permeability

drugs

• For drugs with a dissolution rate limited extent of absorption, the dissolution rate,

stated as a target drug particle size rather than the dose/solubility ratio, provides a

superior way of analyzing the development risks and CQAs.

The incorporation of above concepts is illustrated in figure below:

12
DCS categorization of selected drugs is illustrated below:

13
Reference

1. Dimond PF. Using nanotechnologies in biotech and medicine. Genetic Engineering News.

25; 2005: 21-28.

2. Amidon GL, Lennernas H, Shah VP, Crison JR. 1995. A theoretical basis for a

biopharmaceutic drug classification system: The correlation of in vitro drug product

dissolution and in vivo bioavailability. Pharm Res 12:413–420.

3. FDA Guidance: Waiver of in vivo bioavailability and bioequivalence studies for

immediate-release solid oral dosage forms based on a biopharmaceutics classification

system. Issued Aug. 2000, see http://www.fda.gov/cder/guidance/.

4. Butler, J. M., & Dressman, J. B. (2010). The Developability Classification System:

Application of Biopharmaceutics Concepts to Formulation Development. Journal of

Pharmaceutical Sciences, 99(12), 4940–4954. doi:10.1002/jps.22217 Amber Vyas, Bina

Gidwani. Technologies to Counter Poor Solubility Issues: A Review. Research J. Pharm.

and Tech. 6(11): November 2013; Page 1258-1270.

5. Ain S, Ain Q, Parveen S. An overview on various approaches for solubilization of poorly

soluble drugs. The Pharma Research Journal. 2; 2009: 84- 104.

6. Singhal D, Curatolo W. Drug polymorphism and dosage form design: a practical

perspective. Advanced Drug Delivery Reviews. 56; 2004: 335—347.

7. S. R. K. Yellela, “Pharmaceutical technologies for enhancing oral bioavailability of poorly

soluble drugs,” Journal of Bioequivalence & Bioavailability, vol. 2, no. 2, pp. 28–36, 2010.

8. K. H. Edward and D. Li, “Solubility,” in Drug Like Properties: Concept, Structure, Design

and Methods, from ADME to Toxicity Optimization, p. 56, Elsevier, 2008.

14
9. V. R. Vemula, V. Lagishetty, and S. Lingala, “Solubility enhancement techniques,”

International Journal of Pharmaceutical Sciences Review and Research, vol. 5, no. 1, pp.

41–51, 2010.

10. D. Sharma, M. Soni, S. Kumar, and G. D. Gupta, “Solubility enhancement—eminent role

in poorly soluble drugs,” Research Journal of Pharmacy and Technology, vol. 2, no. 2, pp.

220–224, 2009.

11. A. Kumar, S. K. Sahoo, K. Padhee, P. S. Kochar, A. Sathapathy, and N. Pathak, “Review

on solubility enhancement techniques for hydrophobic drugs,” Pharmacie Globale, vol. 3,

no. 3, pp. 001–007, 2011.

12. N. Blagden, M. de Matas, P. T. Gavan, and P. York, “Crystal engineering of active

pharmaceutical ingredients to improve solubility and dissolution rates,” Advanced Drug

Delivery Reviews, vol. 59, no. 7, pp. 617–630, 2007.

13. Kirupakar BR. Nanosuspension drug delivery. Technology and application. Express

Pharma Pulse. 2005.

14. Liversidge, G.G. et al., 1992. US Patent 5,145,684, 22.

15. Ketan T. Savjani, Anuradha K. Gajjar, Jignasa K. Savjani, "Drug Solubility: Importance

and Enhancement Techniques", International Scholarly Research Notices, vol. 2012,

Article ID 195727, 10 pages, 2012. https://doi.org/10.5402/2012/195727

16. Serajuddin ATM. Solid dispersion of poorly water-soluble drugs. Early promises,

subsequent problems and recent breakthrough. Journal of Pharmaceutical Sciences. 88;

1999: 1058-1066.

15
17. Vadnere MK. 2002. Encyclopedia of pharmaceutical technology, 2nd ed., Marcel Dekker

Inc., Newyork, pp. 132

18. A. M. Abdul-Fattah and H. N. Bhargava, “Preparation and in vitro evaluation of solid

dispersions of halofantrine,” International Journal of Pharmaceutics, vol. 235, no. 1-2, pp.

17–33, 2002.

19. McHugh, M., & Krukonis, V. (2013). Supercritical fluid extraction: principles and practice.

Elsevier

20. Perrut, M., Jung, J., & Leboeuf, F. (2005). Enhancement of dissolution rate of poorly-

soluble active ingredients by supercritical fluid processes: Part I: Micronization of neat

particles. International journal of pharmaceutics, 288(1), 3-10.

21. H. Leuenberger, “Spray freeze-drying—the process of choice for low water soluble drugs?”

Journal of Nanoparticle Research, vol. 4, no. 1-2, pp. 111–119, 2002.

22. M. Mumenthaler and H. Leuenberger, “Atmospheric sprayfreeze drying: a suitable

alternative in freeze-drying technology,” International Journal of Pharmaceutics, vol. 72,

no. 2, pp. 97–110, 1991.

23. R. Q. Williams, “Process for production of nanoparticles and microparticles by spray

freezing into liquid,” US Patent no. 20030041602, 2003.

24. K. Uekama, F. Hirayama, and T. Irie, “Cyclodextrin drug carrier systems,” Chemical

Reviews, vol. 98, no. 5, pp. 2045–2076, 1998.

25. A. A. Rasool, A. A. Hussain, and L. W. Dittert, “Solubility enhancement of some water-

insoluble drugs in the presence of nicotinamide and related compounds,” Journal of

Pharmaceutical Sciences, vol. 80, no. 4, pp. 387–393, 1991.

16
26. A. A. Badwan, L. K. El Khordagui, A. M. Saleh, and S. A. Khalil, “The solubility of

benzodiazepines in sodium salicylate solution and a proposed mechanism for hydrotropic

solubilization,” International Journal of Pharmaceutics, vol. 13, no. 1, pp. 67–74, 1983.

27. Moulton, B., & Zaworotko, M. J. (2001). From molecules to crystal engineering:

supramolecular isomerism and polymorphism in network solids. Chemical Reviews,

101(6), 1629-1658.

28. Desiraju, G. R. (2007). Crystal engineering: a holistic view. Angewandte Chemie

International Edition, 46(44), 8342-8356.

29. El-laithy HM. Self-Nano emulsifying Drug Delivery System for Enhanced Bioavailability

and Improved Hepatoprotective Activity of Biphenyl Dimethyl Dicarboxylate. Current

Drug Delivery. 5; 2008: 170-176.

30. Amin K, Dannenfelser RM, Zielinski J, Wang B. Lyophilization of poly ethylene glycol

mixtures. Journal of Pharmaceutical Sciences. 93 (9); 2004 : 2244-2249.

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