Supplementary information files for A framework for systematic crystal shape tuning – case of Lovastatin's needle-shaped crystals

© the authors, CC-BY 4.0Supplementary files for article A framework for systematic crystal shape tuning – case of Lovastatin's needle-shaped crystalsOne of the most important challenges in the pharmaceutical industry is to produce crystals with desired size and shape distributions, to enhance the critical quality attributes of the drug product, such as efficacy, and to improve manufacturability during downstream processing, such as filtration, drying and granulation. The paper provides a framework for effective crystal shape and size tuning, based on a systematic exploration of standard techniques, such as the linear cooling and supersaturation control (SSC), and novel methods based on the systematic combination of several techniques, namely direct nucleation control (DNC), wet milling, SSC and shape modification additives. The crystallization of lovastatin, which is notorious for its challenging needle-shaped crystals, with an extremely high aspect ratio, was used as a case study, and polypropylene glycol (PPG-4000), at different concentrations, was used as an effective shape modifier from small-scale tests studied previously. The proposed techniques were implemented in the case of seeded and unseeded systems. It was demonstrated that the combination of temperature cycling and polymer additive enhances greatly the control over the aspect ratio and crystal size distribution, compared to conventional linear cooling and SSC strategies. The implementation of wet milling at the beginning of the process, or the introduction of seeds, enhances even further the control of the critical quality attributes of the crystalline product.

© 作者版权，CC-BY 4.0 辅助文件：文章《系统化晶体形状调控框架——以洛伐他汀针状晶体为例》之一。制药工业中的一项重大挑战是生产具有所需尺寸和形状分布的晶体，以提升药物产品的关键质量属性，如疗效，并在下游加工过程中如过滤、干燥和造粒中提高可制造性。该论文提供了一种基于对标准技术如线性冷却和过饱和控制（SSC）的系统探索，以及基于几种技术系统组合的革新方法的晶体形状和尺寸调控框架。以洛伐他汀的针状晶体为例，该晶体以其极具挑战性的极高长径比而闻名，该论文通过小规模试验研究了不同浓度的聚丙二醇（PPG-4000）作为有效的形状调节剂。所提出的技术在种子培养和非种子培养系统中得到实施。研究表明，与传统的线性冷却和SSC策略相比，温度循环与聚合物添加剂的组合极大地增强了对外形比和晶体尺寸分布的控制。在工艺初期引入湿磨或引入种子，进一步增强了晶体产品质量属性关键参数的控制。