A Novel Continuous Method for Co-crystal Formation

一种新的连续共晶形成方法

• 批准号: EP/J003360/1
• 负责人: Anant Paradkar
• 金额: $ 63.12万
• 依托单位: University of Bradford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2012
• 资助国家: 英国
• 起止时间: 2012 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FJ003360%2F1
• 关键词: Novel; Continuous; Method; Co; crystal

A high proportion of new drugs being discovered are extremely difficult to develop into viable dosage forms because of their inherently poor properties. Many of these drugs are poorly soluble and therefore the active ingredient is difficult to dissolve, for example in the stomach, which limits its ability to be transferred into the body. There are several potential routes to overcome problems such as poor solubility. These include reducing the size of the drug particles, forming salts or dissolving the drug in a soluble polymer by processes such as freeze-drying. These techniques are generally complex and costly, and are only suitable for some types of drugs.Another potential method of improving the solubility of certain drugs is to form a co-crystal of the drug with another pharmaceutically accepted material, such as a sugar or vitamin. A co-crystal is a new crystalline structure produced from the two forming materials, which is a solid at room temperature. Recently, there has been an increased interest in co-crystal research, reflected by an exponential rise in the number of research publications and patents in this field over the last decade. However, the potential to use these materials has so far been limited by the methods by which co-crystals are produced. These have been restricted to manufacture on a laboratory scale of only a few grams, and have yielded a low purity of co-crystal, with typical conversion rates between 20 and 60%. Such methods include dissolving the two co-formers in a solvent and precipitating out the co-crystals, or grinding the two co-formers together with a small amount of solvent.A new method to produce co-crystals has been developed by an inter-disciplinary team at the University of Bradford consisting of pharmaceutical scientists and process engineers. The technique is based on twin screw extrusion, a well-established process in the plastics industry which is increasingly being used in the pharmaceutical sector. The extrusion process relies upon a combination of high temperature and shearing forces to gradually convert the co-formers into co-crystals. This method has been found to yield co-crystal purities close to 100% in initial experiments with model drugs such as ibuprofen with nicotinamide acting as a co-former. The technique is continuous, readily scalable and solvent-free, and thus lends itself well to industrial scale manufacturing. This research project led by the research team at Bradford aims to explore the underpinning science behind the formation of co-crystals in this innovative process. Using a selection of model drugs and co-formers, the optimum conditions at which co-crystals form will be determined. A range of analytical techniques will be used to characterise the state and structure of the crystalline materials, including novel in-process measurements to quantify the dynamics of formation during extrusion. The pharmaceutical properties of these new co-crystals, such as solubility, drug release rate and stability, will be assessed and suitable downstream processing methods to convert the materials into tablets or other suitable dosage forms will be investigated. The findings of this project will significantly improve the potential for use of co-crystals in commercial drug delivery. Understanding the fundamental mechanisms behind co-crystal formation and subsequent optimisation of this process will accelerate industrial interest in this field, providing direct benefits to the UK pharmaceutical sector and wider long term benefits to public health through the availability of otherwise unusable drugs.

由于其固有的不良性质，很大一部分正在发现的新药极难开发成可行的剂型。这些药物中的许多溶解性差，因此活性成分难以溶解，例如在胃中，这限制了其转移到体内的能力。有几种潜在的途径来克服诸如溶解性差的问题。这些方法包括减小药物颗粒的尺寸，形成盐或通过诸如冷冻干燥的方法将药物溶解在可溶性聚合物中。另一种改善某些药物溶解度的潜在方法是将药物与另一种药学上可接受的材料（如糖或维生素）形成共晶体。共晶是由两种形成材料产生的新的晶体结构，其在室温下为固体。最近，人们对共晶研究的兴趣越来越大，这反映在过去十年该领域的研究出版物和专利数量呈指数增长。然而，迄今为止，使用这些材料的潜力受到制备共晶的方法的限制。这些化合物仅限于以几克的实验室规模生产，并且产生低纯度的共晶，典型的转化率为20 - 60%。这些方法包括将两种共形成物溶解在溶剂中并沉淀出共晶体，或者将两种共形成物与少量溶剂一起研磨。布拉德福德大学的一个由制药科学家和工艺工程师组成的跨学科团队开发了一种生产共晶体的新方法。该技术基于双螺杆挤出，这是塑料行业中一种成熟的工艺，越来越多地用于制药行业。挤出过程依赖于高温和剪切力的组合以将共形成物逐渐转化为共晶体。已经发现该方法在用模型药物如布洛芬与烟酰胺作为共形成物的初始实验中产生接近100%的共晶体纯度。该技术是连续的，易于放大和无溶剂，因此很适合工业规模的生产。由布拉德福德研究团队领导的这项研究项目旨在探索在这一创新过程中形成共晶背后的基础科学。使用选择的模型药物和共形成物，将确定共晶体形成的最佳条件。一系列的分析技术将被用来验证晶体材料的状态和结构，包括新的过程中的测量，以量化在挤出过程中形成的动力学。这些新的共晶体的药物性质，如溶解度，药物释放速率和稳定性，将进行评估，并将研究合适的下游加工方法，将材料转化为片剂或其他合适的剂型。该项目的研究结果将显着提高共晶体在商业药物输送中的应用潜力。了解共晶形成背后的基本机制以及随后对该过程的优化将加速该领域的工业兴趣，为英国制药行业提供直接利益，并通过提供其他无法使用的药物为公共卫生提供更广泛的长期利益。

项目成果

Coformer Replacement as an Indicator for Thermodynamic Instability of Cocrystals: Competitive Transformation of Caffeine:Dicarboxylic Acid

共晶替代作为共晶热力学不稳定性的指标：咖啡因：二羧酸的竞争性转化

• DOI: 10.1021/acs.cgd.6b00458
• 发表时间: 2016
• 期刊: Crystal Growth & Design
• 影响因子: 3.8
• 作者: Alsirawan M

Tracing the Architecture of Caffeic Acid Phenethyl Ester Cocrystals: Studies on Crystal Structure, Solubility, and Bioavailability Implications

• DOI: 10.1021/acs.cgd.6b00759
• 发表时间: 2016-08
• 期刊: Crystal Growth & Design
• 影响因子: 3.8
• 作者: S. Ketkar;Sudhir K. Pagire;N. R. Goud;K. Mahadik;A. Nangia;A. Paradkar

Understanding Matrix-Assisted Continuous Co-crystallization Using a Data Mining Approach in Quality by Design (QbD)

• DOI: 10.1021/acs.cgd.0c00338
• 发表时间: 2020-07-01
• 期刊: CRYSTAL GROWTH & DESIGN
• 影响因子: 3.8
• 作者: Chabalenge, Billy;Korde, Sachin;Paradkar, Anant
• 通讯作者: Paradkar, Anant

Solid-State Competitive Destabilization of Caffeine Malonic Acid Cocrystal: Mechanistic and Kinetic Investigations

• DOI: 10.1021/acs.cgd.0c01246
• 发表时间: 2020-12-02
• 期刊: CRYSTAL GROWTH & DESIGN
• 影响因子: 3.8
• 作者: Alsirawan, Mhd Bashir;Lai, Xiaojun;Paradkar, Anant
• 通讯作者: Paradkar, Anant

Continuous Manufacturing of Cocrystals Using Solid State Shear Milling Technology

使用固态剪切研磨技术连续制造共晶

• DOI: 10.1021/acs.cgd.7b01733
• 发表时间: 2018
• 期刊: Crystal Growth & Design
• 影响因子: 3.8
• 作者: Korde S