Qualification of Non-Halogenated Organic Solvents Applied to Microsphere Manufacturing Process.

Hyunjin Shim,Hongkee Sah

doi:10.3390/pharmaceutics12050425

Abstract

As a non-halogenated dispersed solvent, ethyl acetate has been most commonly used for the manufacturing of poly-d,l-lactide-co-glycolide (PLGA) microspheres. However, ethyl acetate-based microencapsulation processes face several limitations. This study was aimed at proposing ethyl formate as an alternative. Evaluated in this study was the solvent qualification of ethyl formate and ethyl acetate for microencapsulation of a hydrophobic drug into PLGA microspheres. An oil-in-water emulsion solvent extraction technique was developed to load progesterone into PLGA microspheres. Briefly, right after emulsion droplets were temporarily stabilized, they were subject to primary solvent extraction. Appearing semisolid, embryonic microspheres were completely hardened through subsequent secondary solvent extraction. Changes in process parameters of the preparative technique made it possible to manipulate the properties of emulsion droplets, progesterone behavior, and microsphere quality. Despite the two solvents showing comparable Hansen solubility parameter distances toward PLGA, ethyl formate surpassed ethyl acetate in relation to volatility and water miscibility. These features served as advantages in the microsphere manufacturing process, helping produce PLGA microspheres with better quality in terms of drug crystallization, drug encapsulation efficiency, microsphere size homogeneity, and residual solvent content. The present ethyl formate-based preparative technique could be an attractive method of choice for the production of drug-loaded PLGA microspheres.

Highlights

There have been wide interests in development of poly-d,l-lactide-co-glycolide (PLGA) microspheres as long-acting parenteral depots [1,2,3]
Solubility parameters of PLGA and severaTlimseol(vdaeynst)s are shown in Figure 11. δD is the energy fdoerncseFFiitigbygueufrtrreweo1em10e0..ndDDiimssispssooeollruelusctitiuooiolnnenspbp.roroδonfHfiidllesresesbopoefrftpewpsrroeeognegentessstmteterhroooelnneeeecnuoobelbesrssege,ryrvavenefdrddowwmδiPitthhihs(y( tdh))reEEoeFFgnemmenriicgcbrryooossnfpprdohhsmeerrbeedssetiaapwnnoddelea((n r )i)mnEEtAoeAlroemoncneuoeslls.ee.sc.uAlasr reported elsewhere [22,23], the solubility parameters of PLGA 50:50 are [16.38, 9.13, 7.12], and those 4
The Hansen Solubility Parameter (HSP) distances between wPLhGerAessaunbdscEriFptra1nsgeervfreosmas2a.3stiogn7.o8,f wPLhGerAeaasnRdasvuabluscersipotf 2PLstGanAd−sEfAorasreol4v.e0natn. dRa7.3is

Summary

Introduction

There have been wide interests in development of poly-d,l-lactide-co-glycolide (PLGA) microspheres as long-acting parenteral depots [1,2,3]. A metabolite of methylene chloride, triggers adverse health effects Because of these toxicological profiles, the solvent is found in the ATSDR (Agency for Toxic Substances and Disease Registry) 2019 Substance Priority List (#90 out of total 275 hazardous substances). The Department of Health and Human Services (DHHS, USA) considers methylene chloride a human carcinogen Chloroform is another solvent that is qualified for an emulsion-based microencapsulation process, and it is frequently used to prepare polymeric microspheres [6,7,8]. This halogenated solvent (#11 in the ATSDR Substance Priority List), is more toxic than methylene chloride. The ICH classifies methylene chloride and chloroform as Class 2 solvents [9]

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