高溶解度的Dacarbazine多组分晶体较少光降解倾向

Highly Soluble Dacarbazine Multicomponent Crystals Less Prone to Photodegradation

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MOLECULAR PHARMACEUTICS

影响因子:4.5

分区:医学2区 / 药学2区医学：研究与实验3区

发表日期:2024 Jul 01

作者: Luan F Diniz, Paulo S Carvalho, Mateus A C Souza, Renata Diniz, Christian Fernandes

DOI: 10.1021/acs.molpharmaceut.4c00393

keywords: cocrystal; cocrystallization; dacarbazine; salt; solubility; stability

摘要

Dacarbazine（DTIC）是一种广泛应用于晚期恶性黑色素瘤治疗的抗肿瘤药物。然而，该药物具有低且pH依赖的溶解性，以及对光敏感的特性。这些特性意味着在药品制造甚至药物给药过程中会形成非活性光降解产物2-azahypoxanthine（2-AZA）。我们致力于开发具有增强溶解性和溶出行为的新型DTIC盐/共晶体，以克服或最小化这种不良的生物药剂学特性。通过共晶化技术，成功制备了两种盐、两种共晶体和一种盐-共晶体，反应对象为脂肪族羧酸。采用单晶X射线衍射（SCXRD、PXRD）、光谱（FT-IR和^1H NMR）及热分析（热重分析TG和差示扫描量热法DSC）对这些新型多组分晶体结构进行了详细表征。大部分报道的DTIC晶体形式显示出溶解度显著提高（最高19倍），内在溶出速率加快（1.3到22倍），有助于减少DTIC在溶液中的光降解。这些发现增强了这些新固体形式在改善DTIC有限的生物药剂学特性中的潜力。

Abstract

Dacarbazine (DTIC) is a widely prescribed oncolytic agent to treat advanced malignant melanomas. Nevertheless, the drug is known for exhibiting low and pH-dependent solubility, in addition to being photosensitive. These features imply the formation of the inactive photodegradation product 2-azahypoxanthine (2-AZA) during pharmaceutical manufacturing and even drug administration. We have focused on developing novel DTIC salt/cocrystal forms with enhanced solubility and dissolution behaviors to overcome or minimize this undesirable biopharmaceutical profile. By cocrystallization techniques, two salts, two cocrystals, and one salt-cocrystal have been successfully prepared through reactions with aliphatic carboxylic acids. A detailed structural study of these new multicomponent crystals was conducted using X-ray diffraction (SCXRD, PXRD), spectroscopic (FT-IR and 1H NMR), and thermal (TG and DSC) analyses. Most DTIC crystal forms reported display substantial enhancements in solubility (up to 19-fold), with faster intrinsic dissolution rates (from 1.3 to 22-fold), contributing positively to reducing the photodegradation of DTIC in solution. These findings reinforce the potential of these new solid forms to enhance the limited DTIC biopharmaceutical profile.