Aqueous solubility

Module 4 : Pharmaceutical Preformulation : Basics and Industrial Applications

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Aqueous Solubility - Pharmaceutical Preformulation

Aqueous Solubility – Pharmaceutical Preformulation

Part 1

Components of Solubility Studies

Solubility is one of the most critical preformulation properties that have a significant impact on performance of a molecule. Solubility and permeability form the backbone of Biopharmaceutics Classification System (BCS) that provides scientific framework for designing of drug delivery systems and many regulatory decisions. Solubility assessment is one of the first most important and extensively studies, preformulation parameter. Various aspects like aqueous solubility, pH solubility profile, dissociation constant, partition coefficient and solubility in non-aqueous solvents are studied during preformulation.

Solubility and Oral Absorption

Orally administered drug has to first dissolve in gastrointestinal milieu before it can be absorbed. Dissolved drug then permeates through the intestinal membrane, before reaching systemic circulation. Newer tools of drug discovery like combinatorial chemistry and high throughput screening have led to increasing lipophilicity and decreasing aqueous solubility of discovery molecules. Estimates indicate that about 40% of drug molecules fail because of non-optimal biopharmaceutical properties like aqueous solubility. This puts a lot of strain on pharmaceutical development as technological interventions to overcome were solubility have to be employed. Discovery scientists assess the ‘minimum acceptable solubility’ for oral absorption, by considering the permeability and dose of the drug molecule. Various tools like Lipinski’s rule of 5, Dabs (absorbable dose), MAD (maximum absorbable dose) and BCS are employed for solubility related decision-making during drug discovery.

Solubility and Formulation Development

Apart from important role during candidate drug selection, solubility plays a crucial role during formulation development. Parenteral formulations require sufficient aqueous solubility of the drug molecule. Similarly bioavailability from solid formulations like tablets and capsules is also dependent on solubility and dissolution rate. Numerous solubilization techniques are employed for drug molecules exhibiting non-optimal aqueous solubility.

Experimental determination of Aqueous Solubility

For a given solid solute and solvent, the solubility dependent on the intermolecular adhesive interactions between solute-solute, solute-solvent and solvent-solvent molecules. Hence, intrinsic solubility is governed by crystal packing, cavitation energy and solvation energy. Determination of solubility during preclinical (drug discovery) stage is carried out using DMSO based turbidimetry assays. This provides value of kinetic solubility which is an over-estimate of the equilibrium solubility. Automated robotic driven solubility screens have been developed, which provide a rapid means for rank ordering of lead molecules, based on their solubility. Later in the drug development, thermodynamic solubility is determined using traditional shake flask method. Additional studies in fasted state simulating intestinal fluid and the fed state simulated intestinal fluid, are also carried out, to understand role of pH on aqueous solubility.

Dissociation Coefficient (pKa)

Dissociation coefficient is defined as the pH value at which both the ionized and un-ionized species exist in equal amounts. This is an important parameter for ionizable drug molecules, as ionic species differ in solubility, permeability and absorption. Ionized species are more soluble in aqueous medium. In contrast, unionized species cross biological membranes more effectively, because of the fact that the gastro-intestinal membrane acts as a lipoidal sieve barrier. Gastrointestinal milieu exposes the drug molecule to a wide range of pH values. Information on pKa value allows understanding the behavior of ionizable drug molecule, under differential pH conditions.

Part 2

Partition coefficient

Partition coefficient it is an indicator of lipophilicity or hydrophobic bonding of drug molecule. It is expressed as logarithm of P called as log P and signifies distribution constant between and apolar and polar solvent. Log P is the ratio of drug dissolved into immiscible solvents, most commonly it phosphate buffer of pH 7.4 and n-octanol that are in equilibrium. Log P is applicable to unionized compounds. The term D (distribution coefficient) is applicable to ratio of all species unionized and ionized, in two immiscible solvents. Log P and log D are extremely important parameters as they have direct forbearing on interaction with biological membrane and receptor site. Direct correlations have been demonstrated between log P and biological parameters like oral absorption, protein binding and binding to hepatic metabolizing enzymes.

Solubility Studies in non-aqueous solvents

Solubility studies in non-aqueous solvents are important for development of analytical method, crystallization method and formulation development of soluble oral or parenteral formulations. Latter involves solubility assessment in solvents that are approved for use through a particular route of administration.

Conclusion

Solubility because of its importance in drug absorption, performance and formulation development, receives a lot of focus during preformulation studies. An early focus on pharmaceutical developability issues like solubility ensures seamless transition between various stages of drug discovery and development.

Dr. Arvind Bansal

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P.S

Did you get here from a link from a friend, or Twitter? This lesson is part 4 of 11 parts Preformulation Studies Free e-course.  To get more information about it and sign up  Click here.

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