Physical properties of solid molecular dispersions of indomethacin with poly(vinylpyrrolidone) and poly(vinylpyrrolidone-co-vinylacetate) in relation to indomethacin crystallization
Physical properties of solid molecular dispersions of indomethacin with poly(vinylpyrrolidone) and poly(vinylpyrrolidone-co-vinylacetate) in relation to indomethacin crystallization
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DOI：
10.1023/a:1018906132279
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发表时间：
1999-11-01
影响因子：
3.7
通讯作者：
Zografi, G
中科院分区：
文献类型：
--
作者：
Matsumoto, T;Zografi, G
目的。测定吲哚美辛非晶态分子分散体和不同分子量等级的聚（乙烯基吡咯烷酮）PVP、聚（乙烯基吡咯烷酮-醋酸乙烯酯）PVP/VA与30℃下吲哚美辛等温结晶的固态特性。用差示扫描量热法（DSC）测定了分子分散体的玻璃化转变温度（Tg）。利用傅里叶变换红外光谱研究了不同分散体中吲哚美辛与聚合物相互作用的差异。测定了5% w/w和30% w/w聚合物分散体在不同时效时间下的焓弛豫。以纯吲哚美辛和药物中5% w/w的聚合物为物理混合物和分子分散体，进行了定量等温结晶研究。所有共沉淀混合物均呈现单一玻璃化转变温度。所有聚合物都通过氢键与吲哚美辛在固态中相互作用，并在此过程中消除了与吲哚美辛的羧酸二聚体相关的氢键。在低于Tg的16.5℃下，在5% w/w和30%w/w聚合物水平下，分子迁移率相对于单独吲哚美辛降低。在20周的时间内，在任何5% w/w的聚合物分子分散体中，在30℃下均未观察到吲哚美辛的结晶。单独的吲哚美辛和与各种聚合物的物理混合物在2周内完全结晶为这种水平的γ形式。在30℃、5% w/w聚合物水平下，吲哚美辛在分子分散体中的晶体抑制作用的主要基础与聚合物分子量和玻璃化转变温度无关，而更可能与吲哚美辛与氢键的形成能力以及抑制成核和生长所需的羧酸二聚体形成吲哚美辛的伽马晶体形式有关。
Purpose. To measure solid-state features of amorphous molecular dispersions of indomethacin and various molecular weight grades of poly(vinylpyrrolidone), PVP, and poly(vinylpyrrolidone-co-vinylacetate), PVP/VA, in relation to isothermal crystallization of indomethacin at 30 degrees C.Methods. The glass transition temperatures (Tg) of molecular dispersions were measured using differential scanning calorimetry (DSC). FT-IR spectroscopy was used to investigate possible differences in interactions between indomethacin and polymer in the various dispersions. The enthalpy relaxation of 5% w/w and 30% w/w polymer dispersions was determined following various aging times. Quantitative isothermal crystallization studies were carried out with pure indomethacin and 5% w/w polymers in drug as physical mixtures and molecular dispersions.Results. All coprecipitated mixtures exhibited a single glass transition temperature. All polymers interacted with indomethacin in the solid state through hydrogen bonding and in the process eliminated the hydrogen bonding associated with the carboxylic acid dimers of indomethacin. Molecular mobility at 16.5 degrees C below Tg was reduced relative to indomethacin alone, at the 5% w/w and 30%w/w polymer level. No crystallization of indomethacin at 30 degrees C was observed in any of the 5% w/w polymer molecular dispersions over a period of 20 weeks. Indomethacin alone and in physical mixtures with various polymers completely crystallized to the gamma form at this level within 2 weeks.Conclusions. The major basis for crystal inhibition of indomethacin at 30 degrees C at the 5% w/w polymer level in molecular dispersions is not related to polymer molecular weight and to the glass transition temperature, and is more likely related to the ability to hydrogen bond with indomethacin and to inhibit the formation of carboxylic acid dimers that are required for nucleation and growth to the gamma crystal form of indomethacin.