Solubility Enhancement Excipient

 

Introduction:

Poorly soluble drugs are a major issue for the pharmaceutical industry. By using solubility enhancement excipients pharmaceutical formulators can increase the bioavailability of the API. Advanced solubility enhancement excipients can help companies bring products to market faster. Nowadays most of the drug substances are coming into the innovation pipeline with poor water solubility. Here, the influence of excipients will play a significant role to improve the dissolution of poorly aqueous soluble compounds. The drug substance needs to be dissolved in gastric fluids to get the better absorption and bioavailability of an orally administered drug. Dissolution is the rate-controlling stage for drugs which controls the rate and degree of absorption. Usually, poorly soluble oral administrated drugs show a slower dissolution rate, inconsistent and incomplete absorption which can lead to lower bioavailability. The low aqueous solubility of BCS class II and IV drugs is a major challenge in the drug development and delivery process. Several technologies have been used in an attempt to progress the bioavailability of poorly water-soluble drug compounds which include solid dispersions, lipid-based formulations, micronization, solvent evaporation, co-precipitation, ordered mixing, liquid-solid compacts, solvent deposition inclusion complexation, and steam aided granulation. In fact, most of the technologies require excipient as a carrier which plays a significant role in improving the bioavailability. Scientists are therefore focusing on developing formulation strategies for increasing the therapeutic effectiveness of these molecules via an appropriate selection of excipients.

Key Points:

Low aqueous solubility of emerging drugs poses an immense challenge to the pharmaceutical industry. A pharmaceutical active’s bioavailability is often captured in two broad-stroke properties: 

• Permeability and
• Solubility.

The Food and Drug Administration and the pharmaceutical industry as a whole classify most drugs by these two characteristics in a four-quadrant Biopharmaceutical Classification System (BCS).

• Class I: high solubility, high permeability: generally very well-absorbed compounds
• Class II: low solubility, high permeability: exhibits dissolution rate-limited absorption
• Class III: high solubility, low permeability:  exhibits permeability-limited absorption
• Class IV: low solubility, low permeability: very poor oral bioavailability 

Currently, ideal drugs that exhibit high solubility and high permeability (Class I) make up roughly 35% of currently marketed drugs; however, only 10% of future drug candidates in the pipeline are in Class I.

Near about 40% of presently endorsed drugs fall under the BCS class II and IV. In research and development, about 80% of drug compounds channel stated being a poorly soluble in aqueous media which can facilitate efficiency complications of pharmaceutical dosage forms and especially in oral solid dosage (OSD) segment. As an outcome, the oral bioavailability is often quite small for poorly water-soluble active pharmaceutical ingredients (APIs). Therefore, several formulation approaches were established to improve the water solubility. For making an OSD, excipients working as combined carriers. Excipients are from a natural or synthetic or semisynthetic source plays a vital part in pharmacological formulations to improve the water solubility, bioavailability, and stability of low solubility drug products. So, solubilizing technologies along with excipients are building a sustainable growing market opportunity for solubility enhancement in particular APIs. This solubility enhancement excipients trend will have the marketplace at a compound annual growth rate (CAGR) of approximately 13% from 2014 to 2024.

Traditionally, oral solid dosage (OSD) making formulators were addressed most of the solubility challenges by reducing particle-size, converting salt forms and adding surfactants, but most of the people adopted solid dispersion technologies for solubility enrichment of BCS class II and IV compounds. In the process of drug absorption, dissolution place a significant role for lipophilic drugs. Therefore, it is essential to improve the dissolution rate of these drug molecules to make the maximal therapeutic value. Before understanding different methods and technologies for the enrichment of dissolution rate, it is essential to know about dissolution. The process where the solute particles (drug) go into a solution over a period called as dissolution. The drug rate of dissolution is proportionate to drug solubility. Therefore, solubility places a significant role which controls the speed of dissolution, and henceforward it's necessary to improve the absorption as well as the bioavailability of poorly water soluble drugs by using various technologies along with excipients The global pharma excipient market has shown a significant growth in recent years because excipients are increasingly aiding APIs in achieving better functionality, overcoming solubility challenges by providing a product to competitive benefit.

Significance of solubility:

The oral route of drug direction is the maximum favoured process of drug delivery system, but for the case of BCS class II and IV drugs can be tough way due to its poor solubility and thus will lead to less absorption. Therapeutic efficiency of a drug is contingent on the solubility and bioavailability. Typically, the solubility of a drug substance fundamentally depends on the solvent, temperature, and pressure. However, the solubility of the pharmaceutical product directly related to the dissolution rate as per Noyes-Whitney equation, and hence dissolution rate step will play a major role in bioavailability improvement of aqueous solubility.

Selection of right excipients:

Nowadays, most of the people are working towards a pragmatic approach to the selection of polymers for solubility enhancement which consequences in formulators using polymers based on their traditional and reported applications. However, to select the polymers, the following approaches can be beneficial.

• Physicochemical properties of conventional polymers, copolymers, blocks polymers including safety need to study.
• Compatibility and miscibility studies need to perform between poorly soluble drugs and polymers. 

Solid dispersion technologies have commonly used for enhancement of drug bioavailability by using suitable excipients for conversion of amorphous form. Here, the polymer role is to stabilize amorphous form against crystallization and also to progress the dissolution rate by preventing the recrystallization process.

Categories of excipients:

Solubility increasing excipients are comparatively new to the functionalities mentioned above. However, the need of excipients on growing part due to an increase in the growth rate of poorly soluble compounds in oral solid dosage (OSD) submissions. Solubility enhancing excipients mainly categorized into three sections called as a polymer, surfactant, and lipid based. However, polymer-based and lipid-based excipients widely used for solubility enrichment process.

In fact, lipid excipients are the largest category of solubility enhancement excipients because of their large levels of use in drug formulations and their ability to increase the solubility of lipophilic active ingredients. Polymers come in second due to the increasing use of solid dispersion technologies. Foremost function of polymeric excipients was used to stabilize the amorphous APIs and then maintains its supersaturation in an aqueous medium.

Several excipients play a major role pragmatically in improving the solubility and bioavailability of poorly soluble compounds but needs to know better science and judgment in terms of structure, molecules, mode of function, mechanism of excipients and how these excipient work to help in overcoming the issue. Here are some examples of excipient with mode of function for your better understanding:

Hypromellose acetate succinate (HPMC-AS):

Hypromellose acetate succinate is a hydroxypropyl methylcellulose acetate succinate (HPMC-AS) polymer contains four types of semi-randomly substituted 12-28% of methoxy groups (-OCH3), 4-23 % of hydroxypropoxy groups (-OCH2CHOHCH3), 2-16% of acetyl groups (-COCH3) and 4-28% succinoyl groups (-COC2H4COOH).

For structure refer to below figure:

Structure of HPMC-AS

Mode of function:

It places a crucial part in converting to amorphous form from crystalline either by spray dried and or by hot melt extrusion (HME) methods. HPMC-AS proved as an efficient way of producing some stable amorphous solid dispersions for poorly soluble APIs due to the following properties.

• Due to its swelling nature in gastric fluids, it dissolves rapidly in the upper small intestine and thus HPMC-AS solid dispersions carrier act as bioavailability enhancer for poorly water-soluble drugs.
• It has a high glass transition temperature (Tg) at un-ionized state can be able to associate with kind of molecules having less mobility and forms an exceptional physical stability through spray-dried dispersions (SDDs).
• It is having high solvable in volatile diluents like acetone, methanol, ethanol, and thus permits for cost-effective and controlled processes to form SDDs.
• It permits unsolvable drug molecules to interact with the hydrophobic areas of polymer to form stable colloids in aqueous media due to its amphiphilic nature.
• HPMC-AS is a unique polymer in making amorphous solid phase dispersions.

Hydroxypropyl methylcellulose (HPMC):

Hydroxypropyl methylcellulose (HPMC) is a combination of methyl and hydroxypropyl ether. It is semisynthetic, inert, and viscoelastic cellulose molecule.

For structure refer to below figure:

Structure of HPMC

HPMC used as a solid dispersion solubilizer in spray-dried or/and hot melt extrusion (HME) formulations.

• It acts as a hydrogen bond acceptor, donor, superior stabilizer, supersaturation inhibitor, chemically inert to most of the molecules in solid dispersion formulations.
• pH independent dissolution in solid dispersions.
• The low-viscosity grade of HPMC acts as a surfactant which can enhance the wetting properties of the drug and thus improves the solubility.

Crospovidone:

It is a form of cross-linked homopolymer made up synthetically with N-vinyl-2-pyrrolidinone.

For structure refer to below figure:

Structure of Crospovidone

Mode of function:

It is a unique superdisintegrant with high interfacial action which can able to improve the dissolution rate of low solvable compounds. It can act as an amorphous form stabilizer for few drugs by inhibition of drug re-crystallization. It improves the wettability of hydrophobic drugs and thus improves the solubility.

Conclusion:

By nature, most of the excipients might be inert. It is essential to know that the excipients are not only for bulking up the formulation but also place a vital part in the bioavailability enhancement of BCS class II and IV drug molecules through a pragmatic way of experimentations. A combination of good science and good judgment help in overcoming the challenge posed by poorly soluble drugs and meeting stringent development timelines.

Query:

Ask if you have any Query visit  http://pharmasolution1.blogspot.com, I will revert back to you with a solution. To learn more always visit and connect with Pharma solutions by Dr. Ajay.

Legal Barrier:

A legal barrier to copying of this article.

About the Author:

Dr. Ajay Kumar Singh, M.Sc. (Gold Medalist), Ph.D. is the author and founder of “Pharma Solutions by Dr. Ajay”.

Need Help:

Ask Question

Disclaimer:

Examples used in this article are not meant to be endorsements of any product or technology from the author.