Preparation and characterization of spray-dried co-amorphous drug-amino acid salts
Preparation and characterization of spray-dried co-amorphous drug-amino acid salts
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DOI：
10.1111/jphp.12458
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发表时间：
2016-05-01
影响因子：
3.3
通讯作者：
Lobmann, Korbinian
中科院分区：
文献类型：
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作者：
Jensen, Katrine Tarp;Blaabjerg, Lasse Ingerslev;Lobmann, Korbinian
目的近年来，共无定形药物-氨基酸混合物被引入作为其他无定形稳定化方法的一种很有前途的替代方法，如使用聚合物形成玻璃溶液。到目前为止，这些共非晶混合物主要是通过实验室规模的振动球磨制备的。在本研究中，喷雾干燥是一种放大制备非晶态吲哚美辛-氨基酸混合物的方法。此外，还研究了不同共非晶态体系的物理化学性质，考察了氨基酸形成共非晶态盐的能力。方法采用差示扫描量热法、热重分析和X射线粉末衍射法对混合物的固相性质进行表征。用傅里叶变换红外光谱分析了分子间的相互作用。主要研究结果表明，在精氨酸(Arg)、组氨酸(His)和赖氨酸(Lys)等氨基酸的作用下，Ind可以通过喷雾干燥转变为无定形。固态表征表明，与纯无定形药物相比，所有混合物的玻璃化转变温度都较高，这是由于氨基酸的共同非晶化。此外，药物和氨基酸之间以盐/部分盐的形式形成的分子间相互作用在所有混合物中都被观察到。所有混合物在室温和40摄氏度的干燥条件下都是物理稳定的(>；10个月)。与结晶型和非晶型药物相比，IND-ARG在肠道pH条件下的本征溶出度显示出更好的溶出行为。另一方面，IND-LYS和IND-HIS显示，由于IND在溶出过程中的重结晶，IND的本征溶出速度没有显著提高。结论药物与共无定形制剂在溶解过程中持续存在的强烈的分子间相互作用对于防止共无定形制剂的重结晶和提高其溶出度至关重要。
Objectives Recently, co-amorphous drug-amino acid mixtures were introduced as a promising alternative to other amorphous stabilization approaches such as the use of polymers to form glass solutions. So far, these co-amorphous mixtures have been mainly prepared via vibrational ball milling on a lab scale. In this study, spray-drying was investigated as a scale up preparation method for co-amorphous indomethacin (IND)-amino acid mixtures. In addition, the physico-chemical properties of the different co-amorphous systems were investigated with respect to the amino acids' ability towards co-amorphous salt formation.Methods The mixtures were characterized for their solid state properties using differential scanning calorimetry, thermogravimetric analysis and X-ray powder diffraction. Fourier-transform infrared spectroscopy was used to analyze molecular interactions. Furthermore, intrinsic dissolution behaviour, and physical stability at various storage conditions, were examined.Key findings Results showed that IND could be converted into an amorphous form in combination with the amino acids arginine (ARG), histidine (HIS) and lysine (LYS) by spray-drying. Solid state characterization revealed elevated glass transition temperatures for all mixtures compared with the pure amorphous drug due to co-amorphization with the amino acids. Furthermore, strong intermolecular interactions in the form of salt/partial salt formation between the drug and amino acids were seen for all blends. All mixtures were physically stable (>10 months) at room temperature and 40 degrees C under dry conditions. Intrinsic dissolution of the co-amorphous mixtures showed an improved dissolution behaviour under intestinal pH conditions for IND-ARG compared with the crystalline and amorphous forms of the drug. On the other hand, IND-LYS and IND-HIS revealed no significant improvement in the intrinsic dissolution rate of IND due to recrystallization of IND during dissolution.Conclusions It could be shown that strong intermolecular interactions between drug and co-amorphous coformer that persist during the dissolution are crucial to prevent recrystallization and to enhance dissolution of a co-amorphous formulation.