Solubility Enhancement of Nevirapine by Solid Dispersion Technique

Shaikh Aminoddin Raisoddin*, Shifa Maniyar, Sayeeda Begum, Naziya Shaikh

Bangi College of Pharmacy, Vijayapur 586101 (KA) INDIA

*Correspondence: aminshaikh82821@gmail.com

INTRODUCTION

Oral drug delivery stands as the cornerstone of pharmaceutical administration due to its widespread acceptance and numerous advantages. It offers convenience, patient compliance, cost-effectiveness, and non-invasiveness, making it the preferred choice for delivering a wide range of pharmaceuticals [1]. Despite these benefits, the effectiveness of oral drug delivery systems can be hindered by challenges such as poor solubility and low bioavailability of drug substances [2]. Solubility, in particular, plays a critical role in determining the absorption and pharmacokinetic profiles of drugs, directly impacting their therapeutic efficacy [3,4]. A substantial proportion of drugs currently in development, approximately 40% of those on the market and 90% in the pipeline, are characterized by poor water solubility [6]. Historically, failures in drug development have often been attributed to these biopharmaceutical challenges, emphasizing the urgent need for effective solubility enhancement strategies [7].

The Biopharmaceutical Classification System (BCS) categorizes drugs based on their solubility and permeability characteristics, offering a framework to understand and predict their behaviour in the gastrointestinal tract [10]. Drugs falling into Class II (low solubility, high permeability) present specific challenges due to their limited solubility, which can lead to dissolution rate-limited absorption [10]. Overcoming these solubility issues is crucial for optimizing drug delivery via the oral route, necessitating innovative approaches to enhance solubility and thereby improve bioavailability [8].

This review explores various techniques employed to enhance the solubility of poorly water-soluble drugs. These techniques encompass physical modifications such as particle size reduction and crystal engineering, chemical modifications including salt formation and pro-drug synthesis, and advanced nanotechnology-based approaches like nanosponges and nanocrystals [11]. Among these approaches, solid dispersion technology emerges as a promising strategy to enhance solubility by dispersing drug molecules in an inert matrix, thereby improving dissolution rates and ultimately bioavailability [12].

By critically analysing these techniques, this review aims to provide a comprehensive understanding of the current landscape in solubility enhancement strategies, highlighting their applications, advantages, and limitations in the context of oral drug delivery. Through such insights, researchers and pharmaceutical developers can leverage these advancements to address the persistent challenges posed by poorly water-soluble drugs and pave the way for improved therapeutic outcomes.

Approaches for Solubility Enhancement of Poorly Soluble Drugs

Physical Modifications:

1. Particle Size Reduction:

- *Micronization: * This process reduces the particle size of the drug to increase the surface area, which can enhance the dissolution rate and bioavailability.

- *Son crystallization: * Utilizing ultrasonic waves to produce smaller and more uniform crystals, which improve solubility and dissolution rates.

2. Crystal Engineering:

Modification of Crystal Habit: Altering the external shape of crystals can influence the dissolution rate.

Polymorphs: Different crystal forms of the same drug substance can have varying solubility profiles.

Pseudo polymorphs: Inclusion of solvent molecules within the crystal structure can enhance solubility.

3. Drug Dispersion in Carriers:

Eutectic Mixtures: * Combining two or more components to form a mixture with a lower melting point, enhancing solubility.

Solid Dispersions: Dispersing the drug in an inert carrier matrix to improve dissolution rate and bioavailability.

Solid Solutions: A molecular mixture of drug and carrier that can improve solubility and stability.

4. Complexation:

Cyclodextrins: Using complexing agents like Cyclodextrins to form inclusion complexes with drugs, which enhance solubility.

5. Lipid-Based Systems:

Micro emulsions: Stable, isotropic mixtures of oil, water, and surfactants that improve drug solubility.

Self-Emulsifying Drug Delivery Systems (SEDDS): Formulations that spontaneously form fine oil-in-water emulsions upon contact with gastrointestinal fluids, enhancing solubility and absorption.

Chemical Modifications:

1. Formation of Salts and Pro-drugs:

Converting drugs into more soluble salt forms or chemically modifying them into pro-drugs that are more soluble.

2. Cosolvency:

Using solvents in which the drug is more soluble to enhance the solubility in the final formulation.

3. Co-crystallization:

Forming a crystalline structure with another compound that can enhance solubility.

4. Hydrotropy:

Using high concentrations of certain agents (hydro tropes) to increase the solubility of poorly soluble drugs.

5. Solubilizing Agents:

Incorporating agents that enhance solubility through various mechanisms, such as surfactants.

6. Liquisolid Technology:

Converting liquid drugs into free-flowing, non-adherent, dry powder forms by blending with suitable carriers and coating materials.

Nanotechnology-Based Approaches:

1. Nano sponges:

Tiny, porous structures that can encapsulate drugs, enhancing solubility and controlled release.

2. Nanocrystals:

Drugs are formulated as nanoscale crystals, providing a large surface area to enhance solubility and dissolution rate.

3. Nano suspensions:

Sub-micron colloidal dispersions of pure drug particles stabilized by surfactants, improving solubility and bioavailability.

Drug Dispersion in Carriers: Solid Dispersions:

Solid dispersion technology involves dispersing one or more active ingredients in an inert matrix in the solid state to improve dissolution rate, sustain drug release, alter solid-state properties, and enhance solubility and stability. This approach is particularly effective in enhancing the oral bioavailability of poorly water-soluble drugs.

Techniques for Solid Dispersions:

1.      Solvent Evaporation Method:

Developed by Tachibana and Nakamura in 1965, this method involves dissolving both drug and carrier in an organic solvent, followed by evaporation of the solvent to leave a solid dispersion.

2. Spray Drying Method:

A commonly used solvent evaporation technique where the drug and carrier solution is sprayed into a heated air stream, rapidly evaporating the solvent and forming solid dispersions.

3. Freeze Drying (Lyophilisation):

A process where the drug and carrier solution is frozen and then sublimated under vacuum, useful for thermolabile products.

4. Supercritical Fluid Technology:

Using supercritical fluids, like carbon dioxide, to create fine dispersions of the drug in a hydrophilic carrier without residual solvents.

5. Co-precipitation:

Dissolving both the drug and carrier in a solvent, then adding water to precipitate the mixture, which is then filtered and dried.

6. Electrospinning:

Combining solid dispersion technology with nanotechnology to produce drug-loaded fibers by delivering a polymeric fluid stream or melt through a nozzle.

7. Melting Method:

A physical mixture of the drug and carrier is heated until it melts, then rapidly cooled to form a solid dispersion.

8. Hot-Melt Extrusion:

Combining melting with extrusion, where the drug, polymer, and plasticizer are melted and extruded to form amorphous dispersions.

9. Melt Agglomeration Method:

Using a binder as a carrier, where the drug and binder are heated above the melting point of the binder, or a drug dispersion is sprayed onto the heated binder.

10. Kneading Method:

Mixing the carrier into a paste with water, adding the drug, and kneading thoroughly before drying.

11. Melting Solvent Method:

Combining the melting method with solvent evaporation by dissolving the drug in a solvent and incorporating it into the melted carrier.

12. Dropping Method:

A new procedure for creating round particles from melted solid dispersions by dropping the melted mixture onto a cooling plate.

Advantages:

1.      Improved Bioavailability: Enhanced solubility leads to improved drug absorption, bioavailability, and therapeutic efficacy.

2.      Versatility: Various techniques cater to different drug properties and formulation requirements, offering flexibility in formulation design.

3.      Diverse Approaches: From physical modifications to advanced nanotechnologies, a wide array of strategies allows tailored solutions for different drugs.

4.      Cost-Effectiveness: Many techniques utilize existing materials or processes, making them cost-effective compared to developing entirely new drug formulations.

5.      Regulatory Acceptance: Established techniques like solid dispersion technology have a history of regulatory acceptance, facilitating faster approval processes.

Disadvantages:

1.      Complexity: Some techniques, such as nanotechnology-based approaches, may require specialized equipment or expertise, adding complexity to formulation development.

2.      Stability Concerns: Changes in formulation may impact stability, shelf-life, or manufacturing processes, requiring careful consideration and testing.

3.      Scale-Up Challenges: Moving from laboratory-scale to commercial-scale production can present challenges in maintaining consistency and efficiency.

4.      Safety Considerations: Introducing new excipients or materials may raise safety concerns, requiring thorough toxicity and compatibility testing.

5.      Intellectual Property Issues: Innovative techniques may face intellectual property challenges, potentially limiting widespread adoption or collaboration.

CONCLUSION:

In conclusion, the field of solubility enhancement strategies for poorly water-soluble drugs is vast and diverse, encompassing a range of techniques from physical modifications to advanced nanotechnologies. These strategies play a crucial role in overcoming the inherent challenges of drug solubility and bioavailability in oral drug delivery.

Throughout this review, we have explored various approaches including particle size reduction, crystal engineering, salt formation, pro-drug synthesis, Nano sponges, nanocrystals, and solid dispersion technology. Each approach offers unique advantages in enhancing drug solubility, thereby improving dissolution rates and ultimately enhancing therapeutic efficacy.

Applications of these strategies span diverse therapeutic areas, offering tailored solutions to optimize drug absorption and bioavailability. From improving patient compliance to reducing manufacturing costs, these advancements contribute significantly to the pharmaceutical industry's efforts in developing effective oral drug formulations.

Despite their advantages, it's important to acknowledge the Limitations associated with these strategies. Challenges such as complexity in formulation, stability concerns, scale-up issues, safety considerations, and intellectual property challenges necessitate careful evaluation and mitigation strategies during the development and commercialization phases.

Moving forward, continued research and innovation in solubility enhancement strategies will be crucial. This includes further exploration of novel materials, advanced formulation techniques, and comprehensive understanding of drug-excipient interactions. Such advancements will not only address current challenges but also pave the way for improved therapeutic outcomes and patient care.

In conclusion, while the journey towards optimizing oral drug delivery for poorly water-soluble drugs involves complexities and challenges, the benefits are profound. By leveraging these solubility enhancement strategies effectively, researchers and pharmaceutical developers can overcome barriers and contribute to advancing drug delivery technologies, ultimately benefiting global healthcare delivery and patient quality of life.

ACKNOWLEDGMENT

We are thanking to principal and management of Bangi College of Pharmacy, Vijayapur. for providing all necessary facilities during this study.

REFERENCES

1.      Modi Kushai, Modi Monali, Mishra Durgavati, Panchal Mittal, Et Al. Oral Controlled Release Drug Delivery System: An Overview. International Research Journal Of Pharmacy. 2013; 4(3):70-75.

2.      Anand, O., Lawrence, X.Y., Conner, D.P. And Davit, B.M. Dissolution Testing For Generic Drugs: An Fda Perspective. The Aaps Journal. 2011; 13(3): 328.

3.      Kansara, H., Panola, R. And Mishra, A. Techniques Used To Enhance Bioavailability Of Bcs Class Ii Drugs: A Review. International Journal Of Drug Development And Research. 2015; 7(1): 82-93.

4.      Patel, J.N., Rathod, D.M., Patel, N.A. And Modasiya, M.K, Et Al. Techniques To Improve The Solubility Of Poorly Soluble Drugs. International Journal Of Pharmacy & Life Sciences. 2012; 3(2):1459-1469.

5.      Humberstone, A.J. And Charman, W.N. Lipid-Based Vehicles For The Oral Delivery Of Poorly Water Soluble Drugs. Advanced Drug Delivery Reviews. 1997; 25(1): 103-128

6.      Sandeep Kalepu, Vijaykumar Nekkanti. Insoluble Drug Delivery Strategies: Review Of Recent Advances And Business Prospects. Acta Pharmaceutica Sinica B. 2015; 5(5): 442-453.

7.      Nayaz, A., Thakur, R.S. And Koushik, Y. Formulation And Evaluation Of Solubility Enhanced Ciprofloxacin. International Journal Of Pharmaceutical Sciences And Nanotechnology.2013; 6(3): 2131-2136.

8.      Kishor. S. Rathi, Sapana Ahirrao, Sanjay Kshirsagar. Review Article: Solubility Enhancement By Solid Dispersion. Indian Journal Of Drugs. 2018; 6(3): 165-173.

9.      Nikhil K Sachan, A. Bhattacharya, Seema Pushkar, A Mishra. Biopharmaceutical Classification System: A Strategic Tool For Oral Drug Delivery Technology. Asian Journal Of Pharmaceutics. 2009; 2009:76-80.

10.  Kataria Mahesh Kumar, Bhandari Anil. Biopharmaceutics Drug Disposition Classification System: An Extension Of Biopharmaceutics Classification System. International Journal Of Pharmacy.2012; 3(3): 5-10.

11.  Vilas P Bharti, Vinayta R Attal, Anirudha V Munde, Arunadevi S Birajdar. Strategies To Enhance Solubility And Dissolution Of A Poorly Water Soluble Drug. Journal Of Innovations In Pharmaceuticals And Biological Sciences. 2015; 2 (4): 482-494.

12.  Phuong Tran, Yong-Chul Pyo, Dong-Hyun Kim, Sang-Eun Lee Et Al. Overview Of The Manufacturing Methods Of Solid Dispersion Technology For Improving The Solubility Of Poorly Water-Soluble Drugs And Application To Anticancer Drugs. Pharmaceutics. 2019; 11(132):1-26.