药物多晶型与固体制剂的关系研究进展

目的 介绍药物多晶型与固体制剂的关系研究的进展情况。 方法 通过参考 90年代国内外有关文献 ,综述药物多晶型对固体制剂的稳定性、溶出度、生物利用度等性质的影响 ;固体制剂的工艺过程 ,如干燥、粉碎、研磨、压片等亦会影响药物多晶型的特性。 结果 药物多晶型与固体制剂相互影响。 结论 药物多晶型研究与固体制剂的研究意义深远。     

药物多晶型与固体制剂的关系研究进展

目的：介绍药物多晶型与固体制剂的关系研究的进展情况,方法：通过参考90年代国内外有关文献,综述药物多晶对固体制剂的稳定性,溶出度,生物利用度等性质的影响,固体制剂的工艺过程,如干燥,粉碎,研磨,压片等亦会影响药物多晶型的特性,结果：药物多晶型与固体制剂相互影响,结论：药物多晶型研究与固体制剂的研究意义深远。     

对加巴喷丁口服固体制剂处方合理性的浅析

目的：对加巴喷丁口服固体制剂的处方合理性进行分析。方法：采用差示扫描量热法（DSC）、高效液相色谱法（HPLC）与高效液相色谱-质谱联用法（HPLC—MS）对加巴喷丁口服固体制剂所用辅料与加巴喷丁的相容性进行了初步探索。结果：加巴喷丁胶囊与片剂的一些辅料与加巴喷丁不相容,辅料的选择、辅料的质量对药品质量影响很大。结论：加巴喷丁口服固体制剂的质量控制应从处方前研究做起。     

FDA关于普通口服固体制剂生物等效豁免的相关政策介绍

目的介绍FDA关于普通口服固体制剂生物等效豁免的相关政策。方法FDA针对普通口服固体制剂的生物等效豁免先后出台了4个指导原则,对其主要内容进行介绍,并说明起草背景。结果与结论自生物药剂分类系统（BCS）提出以来,对于普通口服固体制剂采用体外溶出对比研究来替代体内生物等效性研究（即生物等效豁免）已成为可能。     

FDA《根据BCS豁免速释固体口服制剂体内生物利用度和生物等效性研究的指导原则》介绍

美国食品药品管理局于2017年12月发布了《根据生物药剂学分类系统豁免速释固体口服制剂体内生物利用度和生物等效性研究指导原则》的正式版本。该指导原则指出原料药属于生物药剂学分类系统（BCS）1类（而且制剂是速溶的）和3类（而且制剂是极速溶的）的速释（IR）固体口服制剂的生物利用度（BA）或生物等效性（BE）研究可获得豁免。正式版本对2015年草案版做了许多修订。详细介绍该指导原则的正式版本并标明约30处修订。该指导原则对我国IR固体口服制剂BA或BE研究的豁免和监管有重要参考价值。     

重视对固体口服药物多晶型的研究

通过国内外有关文献资料，介绍药物多晶型对制剂的理化性质、生物利用度的影响，以及影响固体药物晶型的主要因素。只有时药物的多晶型进行质量控制，才能确保药品使用的安全性和有效性。     

药物多晶型的研究现状

多晶型是影响药物质量和药物疗效的重要因素之一.在药物的早期研究与开发阶段对药物多晶型进行研究具有十分重要的意义.本文归纳总结了有关药物晶型研究进展,讨论了药物多晶型对药物的理化性质、生物利用度以及制剂方法和生产工艺控制等的影响,并介绍了固体药物晶型的研究的主要技术手段和进展.     

口服速释固体制剂技术研究与进展

通过检索国内外近年来相关文献,介绍固体分散滴丸、膜剂、口服冻干制剂、分散片、自乳化/自微乳化释药系统（SEDDS/SMEDDS）等口服固体速释制剂的研究与进展,为药学工作者进行相关制剂研究提供参考。     

3D打印技术在口服固体制剂中的应用研究进展

口服固体制剂是临床用药最为常见的剂型。3D打印技术能够通过计算机辅助设计精准调控口服固体制剂的内部构成以及外部形貌，进而控制药物释放性能，实现精准化治疗。近年来，国内外学者制备出了速释、缓控释、复方、中药等众多3D打印口服固体制剂，用于改善传统口服固体制剂存在的不足。随着精准化治疗的发展，3D打印药物制剂逐渐成为研究热点之一。同时，3D打印作为新兴科学技术存在些许不足，亟待科研工作者共同努力解决。本文综述3D打印技术分类及其在口服固体制剂中应用、机遇与挑战，为3D打印技术在口服固体制剂中的研究与应用提供参考依据，为临床个性化给药提供新的思路和技术。     

口服固体速释制剂及其制备技术

介绍了固体分散滴丸,膜剂,口服冻干制剂,分散片,自乳化／自微乳化释药系统（ＳＥＤＤＳ／ＳＭＥＤＤＳ）,干凝胶和干酏剂等口服固体速释制剂的研究与开发。     

溶媒介导相变的应用研究进展

综述溶媒介导相变机制、动力学及其影响因素，揭示药剂开发中溶媒介导相变的影响。通过分析溶媒介导相变机制与动力学，阐明影响动力学的因素以及制药开发中遇到的问题。由于溶媒介导相变在药剂开发中作用很大，它能避免制药开发中的麻烦又能解决相应问题。故溶媒介导相变的进一步研究会对制药开发起到重要作用。     

Phase transformation considerations during process development and manufacture of solid oral dosage forms

The quality and performance of a solid oral dosage form depends on the choice of the solid phase, the formulation design, and the manufacturing process. The potential for process-induced solid phase transformations must be evaluated during design and development of formulations and manufacturing processes. This article briefly reviews the basic principles of polymorphism, defines the classes of phase transformation and the underlying transformation mechanisms, and discusses respective kinetic factors. The potential phase transformations associated with common unit operations employed in manufacturing solid oral dosage forms are highlighted. Specific examples are given to illustrate the importance of solid phases, and process-induced phase transitions in formulation and process development.     

Two new polymorphs and one dihydrate of lenalidomide: solid-state characterization study

Purpose: Lenalidomide (LDM) is a blockbuster drug for multiple myeloma and non-Hodgkin’s lymphoma, and contributed $ 6.974 billion in sales for Celgene in 2016. The aim of this research is to expand the crystal form landscape, characterize the physicochemical properties and thoroughly investigate the potential solid forms transformation for this famous drug.

Materials and methods: In this study, a comprehensive solid-state screening was carried out. The physicochemical properties, stability and phase transformation were fully investigated using powder X-ray diffraction (PXRD), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), solid state nuclear magnetic resonance (solid state NMR) and Infrared Spectroscopic Analysis (IR). Finally the differences of dissolution behavior were compared through powder dissolution test.

Results: Two new anhydrous forms (α and β) and one new dihydrate form (DH) of LDM were discovered through a comprehensive solid-state screening experiment. The new discovered DH showed better stability under accelerated storage condition (40 °C/75% RH) and in most organic solvents than other forms. The new discovered form α exhibited faster dissolution rate in the early phase and larger apparent solubility than the currently marketed form.

Conclusions: These new forms exhibit a new chance for drug development in view of their pharmaceutical properties and intellectual property.     

Compression-Induced Polymorphic Transformation in Tablets: Role of Shear Stress and Development of Mitigation Strategies

Our goals were to evaluate the effects of (i) hydrostatic pressure alone and (ii) its combined effect with shear stress during compaction, on the polymorphic transformation (form C → A) of a model drug, chlorpropamide. The powder was either subjected to hydrostatic pressure in a pressure vessel or compressed in a tablet press, at pressures ranging from 25 to 150 MPa. The overall extent of phase transformation was determined by powder X-ray diffractometry, whereas 2D-X-ray diffractometry enabled quantification of the spatial distribution of phase composition in tablets. Irrespective of the pressure, the extent of transformation following compaction was higher than that because of hydrostatic pressure alone, the difference attributed to the contribution of shear stress experienced during compaction. At a compression pressure of 25 MPa, there was a pronounced gradient in the extent of phase transformation when monitored from radial tablet surface to core. This gradient decreased with increase in compression pressure. Four approaches were attempted to minimize the effect of compression-induced phase transformation: (a) site-specific lubrication, (b) use of a viscoelastic excipient, (c) ceramic-lined die, and (d) use of cavity tablet. The ceramic-lined die coupled with site-specific lubrication was most effective in minimizing the extent of compression-induced phase transformation.     

Investigation of excipient and processing on solid phase transformation and dissolution of ciprofloxacin

Ciprofloxacin, a very slightly soluble antibiotics, is known to exist as both anhydrous and hydrous forms. This study was carried out to investigate the solid phase transformation of ciprofloxacin during conventional formulation processing that impacts the performance of solid dosage forms. In addition, alternative processing and formulation options were also evaluated to circumvent phase transformation. Anhydrate and hydrate of ciprofloxacin were characterized using differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), powder X-ray diffraction (PXRD) and powder dissolution. As expected, the anhydrate exhibited significantly higher dissolution rate than the hydrate. However, it rapidly converted to the hydrate upon exposure to aqueous medium. Interestingly, premixing the anhydrate with HPMC in the presence of water or ethanol was found to inhibit the processing-induced phase transition. Further studies demonstrated that wet granulation could be an option for preparing tablets with high loading of ciprofloxacin anhydrate through proper selection of excipients and control of processing conditions. Dissolution study of ciprofloxacin in HPMC based extended release matrix tablets indicated different dissolution rates between tablets containing the anhydrate and hydrate, suggesting transformation to the hydrate was significantly inhibited by HPMC in the gel layer of the hydrated tablets.     

Solution-mediated phase transformation: significance during dissolution and implications for bioavailability

Solubility improvement of poorly soluble drug compounds is a key approach to ensuring the successful development of many new drugs. Methods used to improve the solubility of drug compounds include forming a salt, cocrystal, or amorphous solid. These methods of improving solubility can often lead to a phenomenon called solution-mediated phase transformation, a phase change that is facilitated through exposure to solution. Solution-mediated phase transformation occurs in three steps: dissolution to create a supersaturated solution followed by nucleation of less soluble phase and the growth of that phase. When the growth of the less soluble phase occurs on the surface of the metastable solid, this phenomenon can cause a marked decrease in dissolution rate during in vitro dissolution evaluation, and ultimately in vivo. Therefore, transformation to a less soluble solid during dissolution is an important aspect to consider when evaluating approaches to increase the solubility of a poorly soluble drug. Identification of solution-mediated phase transformation during dissolution is reviewed for powder dissolution, rotating disk method, and channel flow-through apparatus. Types of solution-mediated phase transformation are described in this report, including those involving salts, polymorphs, amorphous solids, and cocrystals. Many experimental examples are provided. Evidence of potential solution-mediated phase transformation in vivo is discussed to better understand the relationship between in vitro dissolution evaluation and in vivo performance.     

Solution-mediated phase transformation of anhydrous to dihydrate carbamazepine and the effect of lattice disorder

This paper describes the kinetics of the solution-mediated phase transformation of the anhydrous monoclinic polymorph of carbamazepine (CBZ(A)) to the dihydrate crystal form (CBZ(D)). Monitoring both solution concentration and solid phase composition identified the steps and mechanisms that control the kinetic processes, and regulate the concentration of drug achieved during dissolution of the metastable solid phase, CBZ(A). The results show that the kinetics and the rate-controlling step for the transformation depend on grinding and storage conditions of CBZ(A). Grinding CBZ(A) shortened the transformation times and changed the rate-controlling step from crystallization of CBZ(D) to dissolution of CBZ(A). Grinding may cause various degrees of disorder in the form of lattice defects and/or amorphous regions. These disordered regions promote the anhydrous to dihydrate transformation by facilitating the surface nucleation of CBZ(D) on freshly ground CBZ(A) and on amorphous CBZ. The concentration-time profiles revealed aging effects on the solution-mediated transformation of ground CBZ(A) that were undetectable by diffraction and thermal analysis. These results have significant consequences on the concentration-time profiles of active pharmaceutical ingredients during dissolution of metastable solid phases, crystalline or amorphous.     

Solid‐phase precipitation and extraction,a new separation process applied to the isolation of synthetic peptides

Abstract: A new method for separation and purification is described. The process, referred to as solid‐phase precipitation and extraction (SPPE), was developed and applied to postcleavage isolation of synthetic peptides. The technique uses normal approaches of chromatography and solid‐phase extraction sorbents with a precipitation or drying procedure so that the sorbent becomes a support matrix for thin‐film deposition of the compounds of interest. This procedure causes precipitated compounds of interest to be trapped on the large surface area or in the pores of the matrix so that by‐products and impurities can be removed by strong wash solvents. In application to solid‐phase peptide synthesis chemistry, by‐products from the cleavage and deprotection are selectively extracted from the crude sample mixture under mild conditions. In comparison to the ether precipitation method used in peptide chemistry, the SPPE process provides isolated products that are 14–17% (w/w) higher purity.     

Piroxicam cocrystals with phenolic coformers: preparation,characterization, and dissolution properties

This study explores the preparation and investigation of dissolution properties of piroxicam cocrystals. Differential scanning calorimetry (DSC) was used to determine the capability of resorcinol (RES), methylparaben (MPB), and vanillin (VAN) to form cocrystals with piroxicam (PRX). Generation of cocrystals was attempted by liquid assisted grinding and slurry methods. Cocrystals were characterized by thermal methods, powder X-ray diffraction, and Fourier-transform infrared spectroscopy. Apparent solubility, intrinsic dissolution rate (IDR), and powder dissolution profile of cocrystals were compared with anhydrous piroxicam, piroxicam monohydrate (PRXMH), and previously reported piroxicam-succinic acid cocrystal. Contact angles and particle sizes of the studied solids were also measured. Based on the DSC screening results, we prepared and characterized PRX-RES and PRX-MPB cocrystals. Interestingly, the cocrystals not only failed to improve apparent solubility and IDR of PRX but also showed lower values than PRX that were attributed to induction of phase transformation of PRX to PRXMH. In contrary, cocrystals performed better than PRX in powder dissolution studies. The higher dissolution rates of cocrystals were explained by improved wettability and reduced sizes. This study has highlighted the complexity of solid state properties of cocrystals and has provided new evidence for the in-solution stability issues of cocrystals.     

Understanding processing-induced phase transformations in erythromycin-PEG 6000 solid dispersions

Since the quality and performance of a pharmaceutical solid formulation depend on solid state of the drug and excipients, a thorough investigation of potential processing-induced transformations (PITs) of the ingredients is required. In this study, the physical phenomena taking place during formulation of erythromycin (EM) dihydrate solid dispersions with polyethylene glycol (PEG) 6000 by melting were investigated. PITs were monitored in situ using variable temperature X-ray powder diffraction (VT-XRPD), differential scanning calorimetry (DSC), and hot-stage microscopy (HSM). Possible intermolecular interactions between the drug and polymer in the solid state were further studied by Fourier transform infrared (FTIR) spectroscopy. While in the absence of PEG the dehydration was the only transformation observed, hot-melt processing with the polymer caused the drug to undergo multiple phase transformations (EM dihydrate --> EM dehydrate --> EM anhydrate). This alteration in phase behavior of EM was attributed to the ability of PEG in promoting nucleation and crystal growth of the EM anhydrate through a solvent-mediated route. In situ monitoring of solid dispersion formation, especially by VT-XRPD and HSM, enabled both early-stage detection of phase transformations during the hot-melt processing and better process understanding.