Representative Scale-Down Lyophilization Cycle Development Using a Seven-Vial Freeze-Dryer (MicroFD®)

We have implemented the use of a small-scale, 7-vial Micro Freeze Dryer (MicroFD^®; Millrock Technology, Inc.) that has the capability to accurately control heat transfer during lyophilization. We demonstrate the ability to fine-tune the MicroFD^® vial heat transfer coefficient (K_v) to match the K_v of vials in a LyoStar III laboratory-scale unit. When the MicroFD^® is run under conditions that match the K_v of the LyoStar III, the resulting lyophilization performance between scales results in equivalent product temperature profiles and critical quality attributes for the same drying process. The proposed workflow demonstrates how exploitation of K_v control in the MicroFD^® enables cycle development of at-scale lyophilization processes using only 7 product vials. By changing the MicroFD^® K_v, laboratory and, potentially, manufacturing cycles may be simulated using only 7 product vials for tremendous active pharmaceutical ingredient savings, as long as at-scale heat transfer coefficients are well characterized.     

Applications of the Tunable Diode Laser Absorption Spectroscopy: In-Process Estimation of Primary Drying Heterogeneity and Product Temperature During Lyophilization

The aim of this research was to evaluate the impact of variability in ice sublimation rate (dm/dt) measurement and vial heat transfer coefficient (K_v) on product temperature prediction during the primary drying phase of lyophilization. The mathematical model used for primary drying uses dm/dt and K_v as inputs to predict product temperature. A second-generation tunable diode laser absorption spectroscopy (TDLAS)–based sensor was used to measure dm/dt. In addition, a new approach to calculate drying heterogeneity in a batch during primary drying is described. The TDLAS dm/dt measurements were found to be within 5%-10% of gravimetric measurement for laboratory- and pilot-scale lyophilizers. Intersupplier variability in K_v was high for the same “type” of vials, which can lead to erroneous product temperature prediction if “one value” of vial heat transfer coefficient is used for “all vial types” from different suppliers. Studies conducted in both a laboratory- and a pilot-scale lyophilizer showed TDLAS product temperature to be within ±1°C of average thermocouple temperature during primary drying. Using TDLAS data and calculations to estimate drying heterogeneity (number of vials undergoing primary drying), good agreement was obtained between theoretical and experimental results, demonstrating usefulness of the new approach.     

Freeze-Drying From Organic Co-Solvent Systems,Part 2: Process Modifications to Reduce Residual Solvent Levels and Improve Product Quality Attributes

The use of co-solvent systems can benefit the freeze-drying process and product performance. In this study, cycle designs were applied based on existing recommendations for water-based formulations. Modifications thereof and the influence on the process (e.g., drying times) and product quality attributes (e.g., product appearance, residual solvent) were tested for various cosolvent systems. It was found that fast freezing was associated with the formation of large crystals for 50 mg/g polyvinylpyrrolidone in 40% 1,4-dioxane (w/w), resulting in a 7% reduction of primary drying. The application of high shelf temperatures during primary drying for 50 mg/g polyvinylpyrrolidone in 70% tert-butanol was feasible, resulting in shorter primary drying times but high residual solvent levels (7.7%). Most notable was that the inclusion of an evaporation step after freezing improved the product appearance for low-melting co-solvents (10% ethanol and 10% acetone). No ice or solvent nucleation occurred in the case of 50 mg/g mannitol in 50% N,N-dimethylacetamide during the normal freezing stage. Instead, the solution viscosity significantly increased after cooling to low shelf temperatures, followed by product evaporation (rather than sublimation) during the drying phase and failure to form a product cake after drying. The application of annealing enabled nucleation and sublimation.     

Crystallization of Cyclophosphamide Monohydrate During Lyophilization

The purpose of this study was to investigate the phase behavior of cyclophosphamide (CPA) during various stages of lyophilization, with special emphasis on obtaining crystalline CPA monohydrate (CPA-MH) in the lyophilized product. Subambient differential scanning calorimetry and low-temperature X-ray diffractometry (LTXRD) were used to study the phase behavior of CPA solution (3.7% w/v). In situ lyophilization in LTXRD chamber was used to monitor the phase transitions occurring during the drying stages. Finally, the implications of these findings were confirmed by freeze-drying the aqueous solution in a laboratory-scale freeze-dryer. The results suggested that CPA remains amorphous during freeze concentration, with a T_g' of ?50°C. However, its crystallization as CPA-MH can be induced by annealing the frozen solution between ?5°C and ?10°C. In situ lyophilization in LTXRD showed that the CPA-MH crystallized during annealing, rapidly dehydrated during primary drying, thereby causing structural collapse. The dehydration of CPA-MH can be prevented by lowering the escaping tendency of water molecules from the crystal lattice of CPA-MH by maintaining the chamber pressure to 300, 400, or 500 mTorr. This study highlights the relationship of process parameters used during lyophilization with the solid form of lyophilized CPA.     

采用聚酰胺除辛芍冻干粉针中赤芍提取物鞣质的工艺研究

目的:研究注射用辛芍冻干粉针聚酰胺法除鞣质工艺。方法:以有效成分芍药苷转移率、鞣质检查、局部刺激性和小鼠异常毒性试验为评价指标,通过聚酰胺除鞣质吸附、解析工艺优化,比较传统除鞣质法和聚酰胺除鞣质法除鞣质效果。结果:聚酰胺法能有效去除样品中的鞣质,芍药苷的转移率明显高于其他方法,而且异常毒性显著降低,制剂的安全性得到有效保证。结论:聚酰胺法除鞣质为中药注射剂除鞣质技术提供了实验依据。     

共溶剂冻干法制备环糊精包合物中叔丁醇残留量影响因素考察

为考察共溶剂冻干法制备环糊精包合物中叔丁醇残留量影响因素，优化处方和工艺，有效控制叔丁醇残留量，本文采用气相色谱法测定冻干样品中叔丁醇残留量，通过调整共溶剂中叔丁醇浓度、环糊精种类、样品分装量、冷冻方式及二次干燥时间，以确定影响叔丁醇残留量的主要因素。结果表明，无定形的包合材料、低的叔丁醇浓度和快速的冷冻方式是导致残留量高的主要因素，而退火是一种很好的降低叔丁醇残留量的技术，二次干燥时间对叔丁醇残留量无明显影响。因此，为保证较低的叔丁醇残留量，制备时宜选择适宜的包合材料、共溶剂浓度和冻干工艺。     

维甲酸固体脂质纳米粒冷冻干燥工艺研究

选用不同辅料作为冻干保护剂，制备维甲酸固体脂质纳米粒冻干品，并考察不同制品的外观、粒径、包封率。以冻干品外观、再分散后的粒径和包封率为评价指标，筛选保护剂的优化处方。结果表明，选择蔗糖、蔗糖＋海藻糖、甘露醇＋海藻糖、甘露醇＋蔗糖为冻干保护剂，冻干纳米粒再分散后粒径减小，包封率与冻干前相比有所降低，含海藻糖处方可大大加快纳米粒的再分散速率，4℃和20℃放置3个月稳定性良好。     

Design of Freeze-Drying Processes for Pharmaceuticals: Practical Advice

Design of freeze-drying processes is often approached with a "trial and error" experimental plan or, worse yet, the protocol used in the first laboratory run is adopted without further attempts at optimization. Consequently, commercial freeze-drying processes are often neither robust nor efficient. It is our thesis that design of an "optimized" freeze-drying process is not particularly difficult for most products, as long as some simple rules based on well-accepted scientific principles are followed. It is the purpose of this review to discuss the scientific foundations of the freeze-drying process design and then to consolidate these principles into a set of guidelines for rational process design and optimization. General advice is given concerning common stability issues with proteins, but unusual and difficult stability issues are beyond the scope of this review. Control of ice nucleation and crystallization during the freezing step is discussed, and the impact of freezing on the rest of the process and final product quality is reviewed. Representative freezing protocols are presented. The significance of the collapse temperature and the thermal transition, denoted Tg', are discussed, and procedures for the selection of the "target product temperature" for primary drying are presented. Furthermore, guidelines are given for selection of the optimal shelf temperature and chamber pressure settings required to achieve the target product temperature without thermal and/or mass transfer overload of the freeze dryer. Finally, guidelines and "rules" for optimization of secondary drying and representative secondary drying protocols are presented.     

米托蒽醌聚乳酸缓释毫微粒针剂的制备

在单因素实验的基础上用均匀设计优化了米托蒽醌聚乳酸缓释微粒的制备方法。空白和载药微粒的平均粒径分别为１２９．９６和１３３．１５ｎｍ;包封率为９９．２３％;载药量为１３．５６％;制备收率为９９．３％。以乳和支架剂制得的冻干针剂外型美观、理化性质稳定,再分散后平均粒径为１５２．０２ｎｍ。用动态透析系统考察了不同分子量聚乳酸毫微粒冻干针剂的体外释药特性,结果显示高分子量聚乳酸微粒的释药速度明显慢于低分子