José L. Toro, Directory, Lachman Consultants01.27.21
Over forty percent (40%) of new chemical entities (NCEs) that are being developed confront the challenge of being poorly soluble in water. These include many anti-cancer drugs, such as monoclonal antibodies and small molecules which are also anti-cancer drugs. The problem with NCEs that are poorly soluble in water is their poor absorption and low bioavailability. Anti-cancer drugs exhibit low water solubility due in part to their large molecular weight.1
The physical characteristics of the NCE to be soluble and permeable are very critical factors in the drug’s efficacy. This has created a significant development challenge to formulators in the pharmaceutical industry. Multiple technologies that have been developed, such as lipid-based systems, nano technologies, micronization, and solid dispersion, have been developed to address the problem of poorly soluble hydrophobic compounds. It is known that the existence of intramolecular hydrogen bonds in drug substances significantly reduce their solubility and bioavailability.
Solid dispersion is one of the most widely used technologies to overcome the poor solubility of these compounds and has been a successful technique in creating formulas that work for oral solid dosage (OSD) forms. Solid dispersion is fundamentally a simple drug-polymer two-compound system, where the drug-polymer interaction is the determining factor in its design and performance. This interaction will affect the dissolution rate of the drug, its bioavailability, and shelf-life.2 This article describes some recent advances related to solid dispersion technologies.
Background
A solid dispersion can be defined as a drug substance that is dispersed in an amorphous polymer matrix. This is commonly called an amorphous solid dispersion (ASD). The drug substance (hydrophobic drug) is found as a molecular dispersion within the polymer (hydrophilic carrier) which increases its solubility and can favorably affect the stability of the drug. This results in an increased surface area of the drug substance, which allows for higher drug solubility and an improved dissolution rate.2
In conventional dissolution of drug substances of oral formulations, once the medium (i.e. water at a given pH) comes in contact with the tablet, spontaneous dissolution of the drug substance occurs. In the case of ASDs there are multiple states by which the drug substance can be dissolved. These include drug-rich particles, suspensions of crystals within the polymer, and micelles. These various states are collectively called a colloidal system. The uptake of the drug substance through the intestinal wall of these colloidal systems are complex and occur through a multi-stage process. The work by Taylor and Zhang has contributed significantly to the fundamental understanding on how ASDs increase the bioavailability of drug substances that by themselves would be poorly soluble and of low bioavailability.3
An ASD should be kinetically stable at normal storage conditions as this is a significant contributing factor for its dissolution profile.4 The stability of the ASD is achieved by the appropriate selection of the polymer excipients, the polymer to drug ratio, and how the polymer/drug dispersion is formulated. The successful dissolution of an ASD when administered orally is determined when first the drug substance and the soluble polymer matrix dissolve rapidly and form a supersaturated solution. The supersaturated solution maintains itself long enough for drug absorption through the intestinal wall. This is called the “spring-and-parachute” concept.5
The selection of the polymer (hydrophilic carrier) has an important effect on the stability of the ASD both during in vitro and in vivo conditions. There are various physical-chemical characteristics of the polymer that must be taken into consideration such as: the glass transition temperature of the polymer (Tg), the anionic/cationic nature of the polymer, the presence of functional groups in the polymer chain, its hydrophilicity, and solubility in common organic solvents, amongst others. There are polymers that serve as a wetting agent to effect solubility of the drug substance being released, while others serve as a stabilizer of the supersaturated drug solution.6
Commonly used polymers in the preparation of ASDs are cellulose derivatives such as hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS) and vinyl polymers such as poly (vinylpyrrolidone) (PVP) and poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA). These various types of polymers allow for maintenance of a supersaturated drug concentration in vivo for an extended period of time.4 The carrier (hydrophilic polymer) and the drug substance (hydrophobic substance) are released as fine colloidal particles. The increased surface area these fine particles provide enhance the bioavailability of the drug, improving the drug absorption through the gastrointestinal tract and potentially reducing secondary side effects.7
Advantages of ASDs
ASDs can be manufactured using various processes such as melt extrusion, spray drying, solvent impregnation, freeze-drying, and milling. Spray drying and melt extrusion manufacturing processes are mostly used in large scale manufacturing processes, in particular, solid oral dosage forms which tend to be more accessible to patients.
Spray drying technologies require the drug substance to dissolve in a solvent and the hydrophilic polymer to dissolve in water. The solutions are then mixed by either sonication or other methods to create a liquid, or a suspension/emulsion. Spray drying is defined as an operation in which a liquid stream is divided into very fine droplets via atomization into a glass compartment where they come in contact with hot gas to form a dried fine particle. These particles are further separated from the drying gas using a cyclone or a bag filter.8 Spray drying can be achieved in either open systems for aqueous solutions or in a closed loop system when organic solvents are used. Spray drying offers the benefits of low temperatures for drying and lower exposure times in the hot gases. The use of spray drying renders a fast-drying process and is important in the prevention of any potential phase separation between the drug substance and the polymer.2
Melt extrusion requires that the drug substance be heat stable and has a low melting point. The basic principle of melt extrusion is melting together the drug and the polymer at a temperature slightly above its eutectic point and mixing the liquified solution. The solution is subsequently cooled to form a solid mass. The mass is then crushed, milled, and sieved to achieve the desired particle size.9 The benefits of this method is its simplicity and low cost.
Disadvantages of ASDs
ASDs can be physically instable, affecting the overall stability of the drug product. ASDs have shown to sometimes crystallize out the drug substance and adversely affect the dissolution rate and absorption of the drug.11
ASDs are known to be sensitive to temperature and humidity during storage. This, in turn, can promote phase separation and crystallization of the drug substance, resulting in a decreased solubility and dissolution rate of the drug substance.
Recent advances in ASD technologies
Several recent publications have provided and referenced the substantial evidence on three main mechanisms involved in the dissolution of ASDs.10,11
a) Carrier Controlled Release: In this process water ingresses the polymer (hydrophilic) and induces the formation of a highly viscous gel. The drug substance diffuses to the media usually in a slow process and will depend on the concentration of the drug substance in the ASD and the volume of the medium used for dissolution.
b) Dissolution Controlled Release: In this process the drug substance and the polymer are released simultaneously into the dissolution media. This leads to a supersaturation effect. The supersaturation concentration is likely controlled by total drug substance in the ASD and the volume of the medium used for dissolution. The polymer may be serving as a stabilizer of the supersaturated state.
c) Drug Controlled Release: In this process the polymer and drug substance—depending on its solubility—will dissolve first into the medium and the remaining drug substance of the ASD will be released at a controlled rate. In this mechanism of dissolution, the risk of drug substance crystallizing out of solution can adversely affect the absorption of the drug in the patient.
In a recent publication, Ghobashy et.al. wrote that by irradiating PVP in varying doses the in vitro dissolution of poorly soluble Amlodipine drug substance was improved.12 By gamma irradiation at various doses, there is an induced irradiation-driven ring opening of the PVP. This gives way to free functional groups that may undergo hydrogen-bonding interactions. The assumption is that the scission effect is the major molecular transformation due to irradiation and that no cross-linking of the polymer occurs.13 The term “scission effect” is used in polymer chemistry which describes the degradation of the polymers main chain due to either heat, or ionization by radiation. The cleavage of the polymer main chain forms fragments of the original polymeric chain. The chemical structure of Amlodipine is crystalline and there are strong intramolecular hydrogen bonding interactions which adversely affect the solubility of this drug substance. By using varying gamma irradiated doses of PVP and the formation of the corresponding ASD, the release of Amlodipine into the dissolution medium was significantly improved.
Recent regulatory considerations in the development of ASDs are improving the bioavailability and therapeutic efficiency that many poorly aqueous soluble drug substances present. The physico-chemical properties, such as solubility improvements in ASDs, offer new opportunities for difficult to dissolve drug substances to be considered. The use of Quality by Design (QbD) approaches to the formulation of ASDs provides a systematic approach to development of new drug products.14 The elements of QbD such as quality target product profile, quality risk assessment, Critical Quality attributes, drug substance, polymer and excipients, the ratio of amorphous to crystalline structures, the desired dissolution rates, the ability to successfully manufacture in large scale, and the control strategy are all expected topics in the submission of a NDA using ASD technologies.
Conclusion
The growth of more complex drug substances that are poorly soluble creates a greater need for improvements in drug product manufacturing technologies. Many of the NCEs being discovered, such as anti-cancer drugs, are highly complex and large molecules. The preferred method of administration of any drug is by OSD form. Amorphous spray dispersion continues to address the complex manufacturing of the drug products by offering solutions to manufacture them in OSD forms which allows for dissolution of the drug in water and eventual absorption in the GI tract. The use of gamma irradiation of some polymers and insoluble drug substances presents a potential improvement in the formulation of OSDs and provides enhanced bioavailability of the drug. Also, the use of QbD in the approach to designing these ASD formulations provides a systematic and scientific approach to manufacture these new drug products.
References
1. Tran, P. 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, Vol. 11(3), March 2019, 132.
2. Patel, B. B. et.al. “Revealing facts behind spray dried solid dispersion technology used for solubility enhancement.” Saudi Pharmaceutical Journal, Vol.23(4), September 2015, 352-365.
3. Taylor, L.S. and Zhang, G.G.Z. “Physical chemistry of supersaturated solutions and implications for oral absorption.” Advanced drug delivery reviews, Vol. 101, 2016, 122 – 142.
4. Huang, Y. and Dai, W. “Fundamental aspects of solid dispersion technology for poorly soluble drugs.” Acta Pharmaceutica Sinica B, Vol 4(1), 2014, 18-25.
5. Gauzman, H.R. et.al. “Combined use of crystalline salt forms and precipitation inhibitors to improve oral absorption of celecoxib from solid oral formulations.” Journal of pharmaceutical sciences, Vol. 96(10), 2007, 2686-2702.
6. Mooter, G. “The use of amorphous solid dispersions: A formulation strategy to overcome poor solubility and dissolution rate.” Drug Discovery Today: Technologies, Vol 9(2), Summer 2012, e79 – e85.
7. Dhirendra K. et.al. “Solid dispersions: a review.” Pakistan journal of pharmaceutical sciences, Vol. 22(2), 2009, 234-246.
8. Paudel, A. et.al. “Manufacturing of solid dispersions of poorly water-soluble drugs by spray drying: Formulation and process considerations.” International journal of pharmaceutics, Vol. 453(1), 2013 August 30, 253-284.
9. Serajuddin, A.T.. “Solid dispersion of poorly water-soluble drugs: Early promises, subsequent problems, and recent breakthroughs.” Journal of pharmaceutical sciences, Vol. 88(10), October 1999, 1058-1066.
10. Schittny, A. et.al. “Mechanisms of increased bioavailability through amorphous solid dispersions: a review.” Drug Delivery, Vol. 27(1), 2020, 110-127.
11. Pandi, P. et.al. “Amorphous solid dispersions: An update for preparation, characterization, mechanism on bioavailability, stability, regulatory considerations, and marketed products.” International journal of pharmaceutics, Vol. 586, 2020 August 30, 119560.
12. Ghobashy, MM. et.al. “Improvement of In Vitro Dissolution of the Poor Water-Soluble Amlodipine Drug by Solid Dispersion with Irradiate Polyvinylpyrrolidone.” ACS omega, Vol. 5(34), 2020 September 1, 21476-21487.
13. Mazumbar, N.A. et.al. “Iodine-Incorporated Copolymer of Methyl Methacrylate and N-Vinylpyrrolidone. I. Synthesis and Characterization.” Journal of Macromolecular Science, Part A, Vol. 33(3), 1996, 353-370
14. U.S. Food and Drug Administration, “Guidance for Industry: Q8(R2) Pharmaceutical Development”, November 2009, ICH, Revision 2, https://www.fda.gov/media/71535/download.
José L. Toro, PhD, Director
Lachman Consultants
José L. Toro is a Director in the Compliance Practice at Lachman Consultants who has extensive R&D Quality, and Quality Operations experience in the pharmaceutical industry. Dr. Toro specializes in the transformation of Quality and Technical Services organizations including Quality Systems, global implementations, corporate auditing, technology transfer and plant operations.
The physical characteristics of the NCE to be soluble and permeable are very critical factors in the drug’s efficacy. This has created a significant development challenge to formulators in the pharmaceutical industry. Multiple technologies that have been developed, such as lipid-based systems, nano technologies, micronization, and solid dispersion, have been developed to address the problem of poorly soluble hydrophobic compounds. It is known that the existence of intramolecular hydrogen bonds in drug substances significantly reduce their solubility and bioavailability.
Solid dispersion is one of the most widely used technologies to overcome the poor solubility of these compounds and has been a successful technique in creating formulas that work for oral solid dosage (OSD) forms. Solid dispersion is fundamentally a simple drug-polymer two-compound system, where the drug-polymer interaction is the determining factor in its design and performance. This interaction will affect the dissolution rate of the drug, its bioavailability, and shelf-life.2 This article describes some recent advances related to solid dispersion technologies.
Background
A solid dispersion can be defined as a drug substance that is dispersed in an amorphous polymer matrix. This is commonly called an amorphous solid dispersion (ASD). The drug substance (hydrophobic drug) is found as a molecular dispersion within the polymer (hydrophilic carrier) which increases its solubility and can favorably affect the stability of the drug. This results in an increased surface area of the drug substance, which allows for higher drug solubility and an improved dissolution rate.2
In conventional dissolution of drug substances of oral formulations, once the medium (i.e. water at a given pH) comes in contact with the tablet, spontaneous dissolution of the drug substance occurs. In the case of ASDs there are multiple states by which the drug substance can be dissolved. These include drug-rich particles, suspensions of crystals within the polymer, and micelles. These various states are collectively called a colloidal system. The uptake of the drug substance through the intestinal wall of these colloidal systems are complex and occur through a multi-stage process. The work by Taylor and Zhang has contributed significantly to the fundamental understanding on how ASDs increase the bioavailability of drug substances that by themselves would be poorly soluble and of low bioavailability.3
An ASD should be kinetically stable at normal storage conditions as this is a significant contributing factor for its dissolution profile.4 The stability of the ASD is achieved by the appropriate selection of the polymer excipients, the polymer to drug ratio, and how the polymer/drug dispersion is formulated. The successful dissolution of an ASD when administered orally is determined when first the drug substance and the soluble polymer matrix dissolve rapidly and form a supersaturated solution. The supersaturated solution maintains itself long enough for drug absorption through the intestinal wall. This is called the “spring-and-parachute” concept.5
The selection of the polymer (hydrophilic carrier) has an important effect on the stability of the ASD both during in vitro and in vivo conditions. There are various physical-chemical characteristics of the polymer that must be taken into consideration such as: the glass transition temperature of the polymer (Tg), the anionic/cationic nature of the polymer, the presence of functional groups in the polymer chain, its hydrophilicity, and solubility in common organic solvents, amongst others. There are polymers that serve as a wetting agent to effect solubility of the drug substance being released, while others serve as a stabilizer of the supersaturated drug solution.6
Commonly used polymers in the preparation of ASDs are cellulose derivatives such as hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS) and vinyl polymers such as poly (vinylpyrrolidone) (PVP) and poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA). These various types of polymers allow for maintenance of a supersaturated drug concentration in vivo for an extended period of time.4 The carrier (hydrophilic polymer) and the drug substance (hydrophobic substance) are released as fine colloidal particles. The increased surface area these fine particles provide enhance the bioavailability of the drug, improving the drug absorption through the gastrointestinal tract and potentially reducing secondary side effects.7
Advantages of ASDs
ASDs can be manufactured using various processes such as melt extrusion, spray drying, solvent impregnation, freeze-drying, and milling. Spray drying and melt extrusion manufacturing processes are mostly used in large scale manufacturing processes, in particular, solid oral dosage forms which tend to be more accessible to patients.
Spray drying technologies require the drug substance to dissolve in a solvent and the hydrophilic polymer to dissolve in water. The solutions are then mixed by either sonication or other methods to create a liquid, or a suspension/emulsion. Spray drying is defined as an operation in which a liquid stream is divided into very fine droplets via atomization into a glass compartment where they come in contact with hot gas to form a dried fine particle. These particles are further separated from the drying gas using a cyclone or a bag filter.8 Spray drying can be achieved in either open systems for aqueous solutions or in a closed loop system when organic solvents are used. Spray drying offers the benefits of low temperatures for drying and lower exposure times in the hot gases. The use of spray drying renders a fast-drying process and is important in the prevention of any potential phase separation between the drug substance and the polymer.2
Melt extrusion requires that the drug substance be heat stable and has a low melting point. The basic principle of melt extrusion is melting together the drug and the polymer at a temperature slightly above its eutectic point and mixing the liquified solution. The solution is subsequently cooled to form a solid mass. The mass is then crushed, milled, and sieved to achieve the desired particle size.9 The benefits of this method is its simplicity and low cost.
Disadvantages of ASDs
ASDs can be physically instable, affecting the overall stability of the drug product. ASDs have shown to sometimes crystallize out the drug substance and adversely affect the dissolution rate and absorption of the drug.11
ASDs are known to be sensitive to temperature and humidity during storage. This, in turn, can promote phase separation and crystallization of the drug substance, resulting in a decreased solubility and dissolution rate of the drug substance.
Recent advances in ASD technologies
Several recent publications have provided and referenced the substantial evidence on three main mechanisms involved in the dissolution of ASDs.10,11
a) Carrier Controlled Release: In this process water ingresses the polymer (hydrophilic) and induces the formation of a highly viscous gel. The drug substance diffuses to the media usually in a slow process and will depend on the concentration of the drug substance in the ASD and the volume of the medium used for dissolution.
b) Dissolution Controlled Release: In this process the drug substance and the polymer are released simultaneously into the dissolution media. This leads to a supersaturation effect. The supersaturation concentration is likely controlled by total drug substance in the ASD and the volume of the medium used for dissolution. The polymer may be serving as a stabilizer of the supersaturated state.
c) Drug Controlled Release: In this process the polymer and drug substance—depending on its solubility—will dissolve first into the medium and the remaining drug substance of the ASD will be released at a controlled rate. In this mechanism of dissolution, the risk of drug substance crystallizing out of solution can adversely affect the absorption of the drug in the patient.
In a recent publication, Ghobashy et.al. wrote that by irradiating PVP in varying doses the in vitro dissolution of poorly soluble Amlodipine drug substance was improved.12 By gamma irradiation at various doses, there is an induced irradiation-driven ring opening of the PVP. This gives way to free functional groups that may undergo hydrogen-bonding interactions. The assumption is that the scission effect is the major molecular transformation due to irradiation and that no cross-linking of the polymer occurs.13 The term “scission effect” is used in polymer chemistry which describes the degradation of the polymers main chain due to either heat, or ionization by radiation. The cleavage of the polymer main chain forms fragments of the original polymeric chain. The chemical structure of Amlodipine is crystalline and there are strong intramolecular hydrogen bonding interactions which adversely affect the solubility of this drug substance. By using varying gamma irradiated doses of PVP and the formation of the corresponding ASD, the release of Amlodipine into the dissolution medium was significantly improved.
Recent regulatory considerations in the development of ASDs are improving the bioavailability and therapeutic efficiency that many poorly aqueous soluble drug substances present. The physico-chemical properties, such as solubility improvements in ASDs, offer new opportunities for difficult to dissolve drug substances to be considered. The use of Quality by Design (QbD) approaches to the formulation of ASDs provides a systematic approach to development of new drug products.14 The elements of QbD such as quality target product profile, quality risk assessment, Critical Quality attributes, drug substance, polymer and excipients, the ratio of amorphous to crystalline structures, the desired dissolution rates, the ability to successfully manufacture in large scale, and the control strategy are all expected topics in the submission of a NDA using ASD technologies.
Conclusion
The growth of more complex drug substances that are poorly soluble creates a greater need for improvements in drug product manufacturing technologies. Many of the NCEs being discovered, such as anti-cancer drugs, are highly complex and large molecules. The preferred method of administration of any drug is by OSD form. Amorphous spray dispersion continues to address the complex manufacturing of the drug products by offering solutions to manufacture them in OSD forms which allows for dissolution of the drug in water and eventual absorption in the GI tract. The use of gamma irradiation of some polymers and insoluble drug substances presents a potential improvement in the formulation of OSDs and provides enhanced bioavailability of the drug. Also, the use of QbD in the approach to designing these ASD formulations provides a systematic and scientific approach to manufacture these new drug products.
References
1. Tran, P. 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, Vol. 11(3), March 2019, 132.
2. Patel, B. B. et.al. “Revealing facts behind spray dried solid dispersion technology used for solubility enhancement.” Saudi Pharmaceutical Journal, Vol.23(4), September 2015, 352-365.
3. Taylor, L.S. and Zhang, G.G.Z. “Physical chemistry of supersaturated solutions and implications for oral absorption.” Advanced drug delivery reviews, Vol. 101, 2016, 122 – 142.
4. Huang, Y. and Dai, W. “Fundamental aspects of solid dispersion technology for poorly soluble drugs.” Acta Pharmaceutica Sinica B, Vol 4(1), 2014, 18-25.
5. Gauzman, H.R. et.al. “Combined use of crystalline salt forms and precipitation inhibitors to improve oral absorption of celecoxib from solid oral formulations.” Journal of pharmaceutical sciences, Vol. 96(10), 2007, 2686-2702.
6. Mooter, G. “The use of amorphous solid dispersions: A formulation strategy to overcome poor solubility and dissolution rate.” Drug Discovery Today: Technologies, Vol 9(2), Summer 2012, e79 – e85.
7. Dhirendra K. et.al. “Solid dispersions: a review.” Pakistan journal of pharmaceutical sciences, Vol. 22(2), 2009, 234-246.
8. Paudel, A. et.al. “Manufacturing of solid dispersions of poorly water-soluble drugs by spray drying: Formulation and process considerations.” International journal of pharmaceutics, Vol. 453(1), 2013 August 30, 253-284.
9. Serajuddin, A.T.. “Solid dispersion of poorly water-soluble drugs: Early promises, subsequent problems, and recent breakthroughs.” Journal of pharmaceutical sciences, Vol. 88(10), October 1999, 1058-1066.
10. Schittny, A. et.al. “Mechanisms of increased bioavailability through amorphous solid dispersions: a review.” Drug Delivery, Vol. 27(1), 2020, 110-127.
11. Pandi, P. et.al. “Amorphous solid dispersions: An update for preparation, characterization, mechanism on bioavailability, stability, regulatory considerations, and marketed products.” International journal of pharmaceutics, Vol. 586, 2020 August 30, 119560.
12. Ghobashy, MM. et.al. “Improvement of In Vitro Dissolution of the Poor Water-Soluble Amlodipine Drug by Solid Dispersion with Irradiate Polyvinylpyrrolidone.” ACS omega, Vol. 5(34), 2020 September 1, 21476-21487.
13. Mazumbar, N.A. et.al. “Iodine-Incorporated Copolymer of Methyl Methacrylate and N-Vinylpyrrolidone. I. Synthesis and Characterization.” Journal of Macromolecular Science, Part A, Vol. 33(3), 1996, 353-370
14. U.S. Food and Drug Administration, “Guidance for Industry: Q8(R2) Pharmaceutical Development”, November 2009, ICH, Revision 2, https://www.fda.gov/media/71535/download.
José L. Toro, PhD, Director
Lachman Consultants
José L. Toro is a Director in the Compliance Practice at Lachman Consultants who has extensive R&D Quality, and Quality Operations experience in the pharmaceutical industry. Dr. Toro specializes in the transformation of Quality and Technical Services organizations including Quality Systems, global implementations, corporate auditing, technology transfer and plant operations.
