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Effect of Polymer Hydrophobicity on the Stability of Amorphous Solid Dispersions and Supersaturated Solutions of a Hydrophobic Pharmaceutical.

ABSTRACT: Amorphous solid dispersions of pharmaceuticals often show improved solubility over crystalline forms. However, the crystallization of amorphous solid dispersions during storage, or from elevated supersaturation once dissolved, compromise the solubility advantage of delivery in the amorphous phase. To combat this phenomenon, polymer additives are often included in solid dispersions to inhibit crystallization; however, the optimal properties for polymer to stabilize against crystallization are not fully understood, and furthermore, it is not known how inhibition of precipitation from solution is related to the propensity of a polymer to inhibit crystallization from the amorphous phase. Here, polymers of varied hydrophobicity are employed as crystallization inhibitors in supersaturated solutions and amorphous solid dispersions of the BCS Class II pharmaceutical ethenzamide to investigate the chemical features of polymer that lead to long-term stability for a hydrophobic pharmaceutical. A postpolymerization functionalization strategy was employed to alter the hydrophobicity of poly( N-hydroxyethyl acrylamide) without changing physical properties such as number-average chain length. It was found that supersaturation maintenance for ethenzamide is improved by increasing the hydrophobicity of dissolved polymer in aqueous solution. Furthermore, amorphous solid dispersions of ethenzamide containing a more hydrophobic polymer showed superior stability compared to those containing a less hydrophobic polymer. This trend of increasing polymer hydrophobicity leading to improved amorphous stability is interpreted by parsing the effects of water absorption in amorphous solid dispersions using intermolecular interaction strengths derived from global structural analysis. By comparing the structure-function relationships, which dictate stability in solution and amorphous solid dispersions, the effect of hydrophobicity can be broadly understood for the design of polymers to impart stability throughout the application of amorphous solid dispersions.

SUBMITTER: Frank DS

PROVIDER: S-EPMC6545895 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Effect of Polymer Hydrophobicity on the Stability of Amorphous Solid Dispersions and Supersaturated Solutions of a Hydrophobic Pharmaceutical.

Frank Derek S DS Matzger Adam J AJ

Molecular pharmaceutics 20190115 2

Amorphous solid dispersions of pharmaceuticals often show improved solubility over crystalline forms. However, the crystallization of amorphous solid dispersions during storage, or from elevated supersaturation once dissolved, compromise the solubility advantage of delivery in the amorphous phase. To combat this phenomenon, polymer additives are often included in solid dispersions to inhibit crystallization; however, the optimal properties for polymer to stabilize against crystallization are not ...[more]

PMID: 30645134

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Project description:The maximum achievable concentration of a drug in solution is dictated by the chemical potential of the solid form. Because an amorphous solid has a higher chemical potential than the corresponding crystal form, in the absence of phase transformations, a higher transient solubility is expected. However, the chemical potential of an amorphous drug can be reduced by mixing with another component. Therefore, upon mixing with a polymer to form an amorphous solid dispersion (ASD), the maximum solution concentration achieved can be potentially altered, in particular if the polymer is poorly soluble in the dissolution medium. Such changes in the chemical potential of the drug may be a critical factor in determining the maximum achievable solution concentration, and could alter the crystallization driving force of the drug. Therefore, the aim of this study was to gain insights into the impact of poorly soluble polymers on the "amorphous solubility" of drugs formulated as amorphous solid dispersions. Lopinavir was selected as a model drug with a low crystallization tendency, enabling determination of the amorphous solubility as a function of ASD composition. Model polymers included cellulose acetate (CA), CA phthalate (CAP), ethylcellulose (EC), Eudragit® RL PO (EUD), hydroxypropylmethylcellulose (HPMC), HPMC acetate succinate (HPMCAS), and HPMC phthalate (HPMCP). The "amorphous solubility" of the drug alone was determined and then the changes in maximum achievable concentration were measured as a function of drug loading. Drug-polymer interactions were characterized using infrared spectroscopy (IR), differential scanning calorimetry (DSC) and moisture sorption analysis. The results showed that the maximum achievable concentration ("amorphous solubility") of lopinavir varied with the extent of drug-polymer interactions, as well as the drug weight fraction in the ASD. This information is of great value when evaluating the maximum achievable concentration of amorphous systems formulated with pH responsive polymers, and should contribute to a broader understanding of drug phase behavior in the context of ASDs.

Dataset Information

Effect of Polymer Hydrophobicity on the Stability of Amorphous Solid Dispersions and Supersaturated Solutions of a Hydrophobic Pharmaceutical.

Publications

Effect of Polymer Hydrophobicity on the Stability of Amorphous Solid Dispersions and Supersaturated Solutions of a Hydrophobic Pharmaceutical.

Similar Datasets

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