General understanding on physical stability of pharmaceutical glasses

Ysuo Yoshihshi,Ktsuhide Terd

aInternational Center for Materials Nanoarchitectonics,National Institute for Materials Science,Tsukuba 305-0044,Japan

bFaculty of Pharmaceutical Sciences,Toho University,Funabashi 274-8510,Japan

cInstitute of Medicinal Chemistry,Hoshi University,Tokyo 142-8501,Japan

General understanding on physical stability of pharmaceutical glasses

Kohsaku Kawakamia,*,Takuji Haradaa,b,Mayuko Fukushimaa, Yasuo Yoshihashib,Etsuo Yonemochic,Katsuhide Teradab

aInternational Center for Materials Nanoarchitectonics,National Institute for Materials Science,Tsukuba 305-0044,Japan

bFaculty of Pharmaceutical Sciences,Toho University,Funabashi 274-8510,Japan

cInstitute of Medicinal Chemistry,Hoshi University,Tokyo 142-8501,Japan

A R T I C L E I N F O

Article history:

Available online 23 November 2015

Solid dispersion

Crystallization

Stability

Surface

Although amorphous solid dispersion is one of the most important formulation technologies for poorly soluble drugs[1], the number of marketed oral amorphous formulations is still limited.The lack of an accelerated study protocol for predicting crystallization behavior of amorphous forms has been one of the biggest issues that inhibit their wide use.Isothermal crystallization behavior of pharmaceutical glasses is discussed in this presentation with an eventual aim of predicting physical stability of amorphous dosage forms.

Preparation of glass compounds and determination of crystallinity were done by differential scanning calorimetry(DSC) on aTA Q2000(TA Instruments,New Castle,USA).Glasses were prepared by quenching at 50°C/min from above the melting temperature,followed by annealing in temperature-controlled ovens.The samples were stored in desiccator,in which humidity was controlled by silica-gel or saturated salt solutions. Annealing shorter than 48 hours under the dried condition was performed in DSC.Thermal degradation was negligible for all the compounds.As a comparison,freeze-drying using t-butyl alcohol was also applied for preparing glass samples.

Crystallization behavior of glass materials is determined by a balance of thermodynamic and kinetic factors,for which temperature and local pressure are the dominating factors, respectively[2].Fig.1 shows the time when the crystallinity reached 10%,t10,as a function of the reduced temperature,Tg/T [2].The data for the temperature-controlled compounds fell onto the universal line at least above Tg,meaning that their initiation time can be described as a function of only Tgif the crystallization is governed by thermodynamics.The initiation time for the pressure-controlled compounds was signifcantly longer than that for the thermodynamicallycontrolled ones because of their large energetic barrier for nucleation.However,if the surface area was increased by employing freeze-drying method,the initiation time of thepressure-controlled compounds was shortened to be explained by the universal line as well[3].It was also the case for the samples stored under humid conditions.Thus,the universal line may be regarded as the worst case of crystallization for the pressure-controlled compounds.Attempts to increase stability of pharmaceutical glasses will also be discussed in the presentation.

Fig.1–10%crystallization time(in min,t10)of model compounds as a function of Tg/T.q and FD represent quenched and freeze-dried samples,respectively[2,3].

R E F E R E N C E S

[1]Kawakami K.Modifcation of physicochemical characteristics of active pharmaceutical ingredients and application of supersaturatable dosage forms for improving bioavailability of poorly absorbed drugs.Adv Drug Deliv Rev 2012;64:480–495.

[2]Kawakami K,Harada T,Miura K,et al.Relationship between crystallization tendencies during cooling from melt and isothermal storage:toward a general understanding of physical stability of pharmaceutical glasses.Mol Pharm 2014;11:1835–1843.

[3]Kawakami K.Surface effects on the crystallization of ritonavir glass.J Pharm Sci 2015;104:276–279.

*E-mail:kawakami.kohsaku@nims.go.jp.

Peer review under responsibility of Shenyang Pharmaceutical University.

http://dx.doi.org/10.1016/j.ajps.2015.10.041

1818-0876/©2016 The Authors.Production and hosting by Elsevier B.V.on behalf of Shenyang Pharmaceutical University.This is an open access article under the CC BY-NC-ND license(http://creativecommons.org/licenses/by-nc-nd/4.0/).