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Tailoring supersaturation from amorphous solid dispersions.
J Control Release. 2018 06 10; 279:114-125.JC

Abstract

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.

Authors+Show Affiliations

Department of Industrial and Physical Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, IN 47907, United States.Department of Industrial and Physical Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, IN 47907, United States. Electronic address: lstaylor@purdue.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

29654798

Citation

Li, Na, and Lynne S. Taylor. "Tailoring Supersaturation From Amorphous Solid Dispersions." Journal of Controlled Release : Official Journal of the Controlled Release Society, vol. 279, 2018, pp. 114-125.
Li N, Taylor LS. Tailoring supersaturation from amorphous solid dispersions. J Control Release. 2018;279:114-125.
Li, N., & Taylor, L. S. (2018). Tailoring supersaturation from amorphous solid dispersions. Journal of Controlled Release : Official Journal of the Controlled Release Society, 279, 114-125. https://doi.org/10.1016/j.jconrel.2018.04.014
Li N, Taylor LS. Tailoring Supersaturation From Amorphous Solid Dispersions. J Control Release. 2018 06 10;279:114-125. PubMed PMID: 29654798.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Tailoring supersaturation from amorphous solid dispersions. AU - Li,Na, AU - Taylor,Lynne S, Y1 - 2018/04/11/ PY - 2018/02/19/received PY - 2018/04/06/revised PY - 2018/04/07/accepted PY - 2018/4/15/pubmed PY - 2019/7/23/medline PY - 2018/4/15/entrez KW - Drug release KW - Miscibility KW - Polymer KW - Solubility KW - Thermodynamics SP - 114 EP - 125 JF - Journal of controlled release : official journal of the Controlled Release Society JO - J Control Release VL - 279 N2 - 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. SN - 1873-4995 UR - https://www.unboundmedicine.com/medline/citation/29654798/Tailoring_supersaturation_from_amorphous_solid_dispersions_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0168-3659(18)30196-2 DB - PRIME DP - Unbound Medicine ER -