Advancing Polymers for Solubility Enhancement - Pharmaceutical Technology

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Advancing Polymers for Solubility Enhancement
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.

Pharmaceutical Technology
pp. s6-s11

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.


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