Advancing Polymers for Solubility Enhancement

Poor solubility remains a major challenge in formulation development. As the number of new chemical entities that are poorly soluble keeps increasing, formulation scientists are faced with the important task of addressing these solubility issues so that more compounds can be translated into clinically useful medicines. A popular approach to this problem is to use polymers as solubilizing excipients. Pharmaceutical Technology brought together a panel of industry experts for a special forum to discuss solubilizing polymers and the related formulation strategies for poorly soluble drugs. Participants include Michael Morgen, PhD, director of new technology at Bend Research; Brian Koblinski, strategic marketing manager at Dow Wolff Cellulosics; and Firouz Asgarzadeh, PhD, director of technical services, North America, pharma polymers & services at Evonik Corporation.

Chemical classes and physicochemical properties

PharmTech: Various polymers/copolymers can be used in solubility enhancement. What would you identify as key chemical classes for these excipients and the related properties that contribute to their function as a solubilizer? In what formulation types are they used?

Colin Anderson/Gettyimages

Morgen (Bend Research): Cellulosics, poly(vinylpyrrolidone) (PVP) and its copolymers, acrylates, and poly(ethylene oxide) (PEO) and its copolymers are some of the key classes of polymers that have been investigated as solubilizing excipients for oral formulations. Effective solubilizing polymers tend to be amphiphilic in nature, meaning they have both hydrophobic and hydrophilic sites that enable them to interact favorably with low-solubility (i.e., hydrophobic) compounds and yet disperse and dissolve in aqueous environments such as the gastrointestinal (GI) tract. The specific interactions of the polymer with itself, the API, and the aqueous medium can result in a range of solubilizing structures, including micelles, colloids, and ionic complexes.

Solubilizing polymers are used in many types of formulations, depending on the route of administration, dose, API properties, and specific delivery challenges associated with the particular development program. For oral delivery, solid amorphous dispersions can be an enabling formulation approach for improving the bioavailability of Biopharmaceutics Classification System (BCS) Class II and IV compounds. Two common processes for making such dispersions are spray-drying and hot-melt extrusion (HME). Spray-drying can be used to form a monolithic dispersion particle or alternatively, the dispersion can be deposited onto a solid support to increase surface area and dissolution rate. Two-phase physical mixtures of polymer and crystalline API in a solid dosage form can be used to solubilize the API. For early scoping studies, liquid solutions of polymer (e.g., PEO) and the API may be valuable. In each case, the choice of formulation type and the manufacturing process will depend on the requirements of the specific drug-development program.

Koblinski (Dow): Cellulose-based polymers, such as hypromellose (HPMC) and hydroxypropyl methyl cellulose acetate succinate (HPMCAS, also known as hypromellose acetate succinate) have high utility in solid dispersions. Their safety and low drug reactivity make them an ideal candidate for most drugs. Spray-dried dispersions (SDDs) and HME are the most common technologies for solubilization used with cellulosic polymers. Cellulosic polymers maintain stable solid dispersions, inhibit API crystallization, and can promote supersaturation of the drug. Options in viscosity and substitution levels both with HPMC and HPMCAS help a formulator to optimize performance in solubility enhancement as well as in material processibility, which includes postprocessing SDDs and HME formulations into traditional dosage forms such as tablets and capsules.

Asgarzadeh (Evonik): The chemical structure and physicochemical properties of APIs and polymers play a major role in the formation of polymer-API solid solutions. Poly(meth)acrylates, cellulosic polymers and PVP are extensively used in solid dispersion formulation development. Each class of polymers contains specific chemical bonds that can interact with specific groups on APIs. HME, SDD, and coprecipitation techniques transform poorly-soluble crystalline drugs into an amorphous, metastable, higher-state-of-energy structure dispersed in a polymer matrix that is more easily solubilized, leading to enhanced solubility. Strong hydrogen bonding and ionic interactions between the amorphous API and the polymer would inhibit or retard the recrystallization of the API even with polymers that have low glass-transition temperatures (Tg's). Because there is a myriad of API structures with different physicochemical characteristics, there is not one class of polymers that would be considered better solubilizers than others. It is essential to select appropriate polymers for screening studies based on a good understanding of both the polymer and drug structures and the possible interactions they may have.

Selecting a suitable polymer

PharmTech: What factors determine the type of pharma polymer to use in a given formulation to improve solubility? Can you provide a specific example to illustrate the decision points used in a challenging formulation, including any relevant data?

Morgen (Bend Research): When selecting solubilizing polymers, the performance, stability, and manufacturability of the associated formulation must all be considered. The chemical and physical properties of the solubilizing polymer affect all three of these attributes; hence, it is often necessary to balance polymer properties to achieve the optimum solubilized formulation. Usually, the properties of the API and the requirements of the development program (e.g., dose) will result in greater emphasis on one or two of these three formulation attributes.

Ideally, the solubilizing polymer will interact with the API to sustain elevated API concentrations in the GI tract in one or more high-activity species (e.g., freely dissolved drug, micelles, and colloids). For APIs that are particularly prone to precipitation into a low-energy form, significant polymer/API interaction is especially important. For many APIs, polymers that have a substantial hydrophobic interaction with the API are preferred. HPMCAS is one of the more broadly useful dispersion polymers for forming and sustaining high-energy species in aqueous media with BCS Class II and IV compounds.

Both the chemical and physical stability of solubilized formulations are important. Of the two, chemical stability tends to be more API-specific. Solid-state physical stability is usually an important consideration for solubilized formulations, especially when the drug is in the amorphous state. A key driver for good solid-state physical stability of amorphous forms, such as polymeric dispersions, is low molecular mobility, which can be achieved by choosing a dispersion polymer that has a high Tg. A number of common solubilization polymers, such as PVP and its copolymers and cellulosics, have high Tg in their dry state. Water, however, can plasticize materials and reduce the Tg. Polymers with low-moisture uptake as a function of humidity, such as HPMCAS, often impart better physical stability to amorphous drug forms in the solid state under ambient storage conditions than the more hygroscopic polymers. A high Tg is less important for physical stability when the API and polymer are miscible, which is often the goal for HME formulations.

Manufacturability is an important consideration when selecting solubilization polymers. For spray drying, high solubility and low viscosity in the volatile organic solvents used during processing are important. HME processing requirements are somewhat different, requiring good thermal stability, especially when formulating drugs with high melting temperature (Tm). In addition, the miscibility of the API and polymer is often desirable in HME processing to achieve a single dispersion phase.

Koblinski (Dow): The chemical structure of the API as well as the technology used to achieve improved solubility impact polymer choice. SDD and HME are two common technologies used to create solid dispersions to improve solubility. Each technique has its own set of polymer parameters best suited for use in the technology, yet the overall goals for both methods are to render the drug amorphous, inhibit drug crystallization, and to maximize drug load in the formulation.

Characteristics of polymers best suited for spray drying include the ability to form a sprayable polymer-drug solution. Polymers that result in low-solution viscosity will facilitate higher concentrations of drug and polymer in the solution, thereby reducing solvent usage and increasing formulation versatility.

To be suitable for HME, a pharmaceutical polymer must be melt processable at conditions that do not degrade the formulation components. Polymers with low Tg as well as a broad thermal-processing window are well suited for HME; however, the Tg must be high enough to prevent recrystallization at storage conditions. The polymer must also have good crystal nucleation inhibition to maintain the API at supersaturated levels upon dissolution. Due to a relatively higher polymer content in many HME formulations, polymer safety during processing (i.e., no toxic degradation products) and in the final formulation is also critical.

Asgarzadeh (Evonik): Polymers used for solid-dispersion formation should have reasonably high Tg's to allow the stabilization of the amorphous API structure via molecular motion restriction (i.e., the glassy state) at storage conditions that are usually below the finished product Tg. Polymers with lower Tg's have been shown to form stable solid solutions when strong hydrogen bonding or ionic interactions are formed between the polymer and the active. The strong hydrogen bonding and ionic interactions contribute to the formation and stabilization of solid solutions firstly, by breaking the crystal lattice of poorly-soluble, highly crystalline drugs, and secondly, by delaying the recrystallization as the molecularly dispersed API would prefer to stay bound to the polymer.

Another consideration when using melt extrusion for preparation of solid dispersions is that the polymer Tg should be sufficiently low to allow acceptable processing temperatures minimizing polymer and/or drug degradation. The cationic amino methacrylate copolymer (Eudragit E, Evonik) forms solutions with the anionic drug ibuprofen due to strong hydrogen bonding and ionic interactions at extrusion temperatures as low as 60 °C. Although the Tg's of ibuprofen/Eudragit E solid solution extrudates are as low as 10 °C to 20 °C, they remain amorphous and stable at room temperatures due to the strong hydrogen bonding and ionic interactions. API melting during melt extrusion is not a requirement but helps with solid-solution formation. Solid solutions of drugs with melting point as high as 250 °C to 300 °C is possible when such strong interactions can be formed between polymers and the drug as is the case for sugar and water (solute/solvent) where sugar is not needed to melt in order to be dissolved in water.

Predictive modeling

PharmTech: Can predictive modeling be used in excipient selection of a solubilizing polymer? If so, can you explain the modeling and the related variables used in the model?

Morgen (Bend Research): A range of predictive physical models are helpful in selecting solubilizing polymers. Such models are most valuable when used in conjunction with measured physical properties of the API, the polymer, and/or the formulation. In particular, we often use models to estimate oral absorption based on key parameters, such as API dose, solubility and supersaturation values, API partition coefficient into bile salts, and API dissolution and precipitation rates. Several of these parameters depend on the choice of polymer. In particular, the time profile of the API supersaturation level is often heavily influenced by the choice of polymer and can dramatically affect absorption and bioavailability. These parameters are typically measured in vitro and then used in predictive models. An important caveat is that it is notoriously difficult to accurately predict certain in vivo parameters, such as API precipitation rate based on in vitro measurements. Other types of models that are sometimes employed include solubility parameter approaches to predict interactions between APIs and polymers, including estimates of API solubility in a polymer matrix. Although such predictions can be useful, it is sometimes faster and more accurate to make the measurements than to do the calculations.

Koblinski (Dow): Predictive modeling can be used to calculate polymer–API interactions that may occur. In addition, tools, such as solubility parameters, can be used to establish API solubility in the selected polymer. Hansen solubility parameters are often used in this regard as a screening tool for drug-polymer compatibility, however, they should only be used as a guide in conjunction with preformulation data.

Asgarzadeh (Evonik): In a conventional empirical formulation development approach, various qualitative and quantitative combinations of drug and polymers are melted, spray-dried, or film-casted from organic solvents in numerous experiments to identify appropriate solid solution/dispersion formulations. Such empirical development methodologies are time-consuming and require significant amount of drug as well as costly analyses. Predictive tools to identify solvents for polymers based upon solubility parameters and molecular interactions (e.g., hydrogen bonding and ionic interactions) have been used for several decades in paint, polymer, and organic-chemistry industries. These predictive tools afford faster systematic screening of formulations and processing conditions at the early stages of solid-dispersion product development, independent of the preparation technology used.

One such tool developed by Evonik is MemFis (Melt-Extrusion Modeling and Formulation-Information System). The MemFis model uses well-established polymer and organic-chemistry group contribution theories to estimate Hansen solubility parameters of drug molecules and polymers. In MemFis, the calculations of more than 50 chemical group contributions and the effects of polar (i.e., dipole moments) as well as 40 different hydrogen-bonding interactions on solubility parameters are considered. MemFis enables the selection of initial solid-solution/dispersion formulations and melt-extrusion processing conditions without API consumption. It reduces the number of experiments by bringing quality into formulation development in a systematic rather than empirical approach targeting appropriate experiments. Other analytical tools, such as Raman mapping, differential scanning calorimetry, and atomic force microscopy, can allow early detection of solid-solution formation or any recrystallization effects.

Quality by design

PharmTech: Quality by design (QbD) is an overarching consideration in drug development. With respect to solubility enhancement, what are the critical quality attributes and/or critical process parameters important in excipient selection?

Morgen (Bend Research): Recently, pharmaceutical companies, excipient providers, and CRDMOs (contract research/development/manufacturing organizations) have launched significant initiatives to bring QbD principles to the selection and design of the polymer, the formulation, and the process space. With respect to the polymer, critical quality attributes might include molecular-weight distribution and chemistry attributes, such as the ratio and sequence of different monomeric units and/or the number and substitution pattern of hydrophobic groups on the polymer backbone. There are instances in which relatively small differences in chemistry can significantly affect the performance of the polymer and the formulation. In some cases, the impurity profile of the polymer can also be critical to the performance.

Typically, a number of critical parameters on the process side will influence the choice of excipients. Depending on the process, solvents, and solution temperatures may be selected based on solubility of API or its compatibility with the solvent, which can in turn influence the choice of the polymer. Likewise, process- time–temperature profiles can be critical process parameters, particularly for the choice of HME excipients, to ensure adequate mixing for complete dispersal and dissolution of the API into the heated polymer matrix if a solid solution is desired.

Koblinski (Dow): Selecting the right excipient with control of the critical quality attributes is crucial to a robust formulation. A QbD approach to drug development helps the final drug product to have the desired therapeutic effect on a consistent basis. In solubility enhancement, excipients play the role of stabilizing the drug and keeping it in the desired state to achieve the maximum drug release and concentration sustainment. A QbD study with an excipient, for example HPMCAS, will look at characteristics of the polymer, such as acetyl and succinyl substitution using a design of experiment study to cover the experimental space to find the enhanced substitution levels for solubilization of the specific drug. Through studies done at Dow, we have found some drugs, such as phenytoin, are very sensitive to changes in polymer substitution levels and, therefore, require tight control around the enhanced values for consistent performance. Other less sensitive drugs can tolerate a wider range of substitution values while maintaining performance. A QbD program, in cooperation with the excipient manufacturer, can help formulators develop a robust and therapeutically efficient drug product.

Asgarzadeh (Evonik): When selecting excipients for solubility enhancement, excipient physicochemical properties such as morphological characteristics, aqueous/pH solubility, molecular weight, crystalline structure, porosity, density, and viscosity are amongst the critical quality attributes (CQAs) that should be evaluated. The impact of selected CQAs based upon the risk-assessment survey on the properties of the final product should be studied and well understood. Excipients in a solubility-enhanced formulation should not be considered as fillers or part of the binding matrix anymore because they contribute to the performance of API that otherwise does not have any absorption and bioavailability. The critical process parameters (CPPs) are process specific attributes. For solubility-enhancement applications, melt extrusion and spray drying are the most commonly used technologies. The CPPs for melt extrusion are the screw speed, extrusion temperature, feed rate, glass-transition temperature of the drug-polymer mixture, and melt viscosity. For spray drying however, parameters such as spray rate, percent solids content, size, and scale of the spray dryer, nozzle size and temperature in the expansion chamber should be considered.