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Poly(Lactic Acid) (PLA) for biomedical application – synthesis of biocompatible Mg catalyst and optimization of its use in polymerization of lactide with aid of DOE. Agnieszka Gadomska-Gajadhur, Ludwik Synoradzki, and Pawe# Ru#kowski Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.8b00165 • Publication Date (Web): 09 Aug 2018 Downloaded from http://pubs.acs.org on August 9, 2018
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Organic Process Research & Development
Poly(Lactic
Acid)
(PLA)
for
biomedical
application – synthesis of biocompatible Mg catalyst
and
optimization
of
its
use
in
polymerization of lactide with aid of DOE. Agnieszka Gadomska-Gajadhur, Ludwik Synoradzki and Paweł Ruśkowski* Laboratory of Technological Process, Faculty of Chemistry, Warsaw University of Technology, ul. Noakowskiego 3, 00-664 Warsaw, Poland.
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Table of Contents
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Organic Process Research & Development
KEYWORDS: poly(lactic acid), ROP, magnesium compounds, biomedical applications, DOE,
ABSTRACT: Efficient, original synthesis of magnesium 2-ethylohexanoate via reaction of metallic magnesium with 2-etylohexanoic acid was achieved. The activity of MgOct2 as biocompatible catalyst of lactide ring opening polymerization was examined. The process was successfully optimized by using factorial and rotatable designs. PLA of Mw=34 000 g/mol with high lactide conversion (>95%) has been obtained. Due to the use of biocompatible catalyst (lack of tin), it can be used in medical and pharmaceutical application.
INTRODUCTION Polylactide (PLA) belongs to biodegradable, aliphatic polyesters, whose repeat unit is αhydroxy acid (lactic acid, 2-hydroxypropane). It is called "double green", because it is obtained from renewable sources and degrades to the products of natural origin.1,2 Due to its non-toxicity, high compatibility with human tissues, and the fact that it is easily degraded, PLA has found many applications, including: in the production of packaging,1,3 textiles,4 composites.5 Medicine3,6-6 and pharmacy9,10 form an extremely vigorously developing group of PLA applications. The discovery of recent years are both intelligent drug delivery systems (DDS) and the production of scaffolds for cell cultures.11-15 The stents produced from polylactide with the addition of polyglycolide (PGA)16 and active substances7,17,18 such as ibuprofen,19,20 ketoprofen21-23 or steroid hormones (β-estradiol)24 are of unflagging interest. Polylactide can be obtained in a direct reaction of lactic acid, catalyzed with tin or zinc oxide. Such obtained polymer, however, has low molecular weight, less than 5 000 g/mol.25 A more efficient method of synthesis is polymerization with lactide ring opening (ROP), catalyzed by tin
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(II) 2-ethylhexanoate (Oct2Sn).27 Thereby, a polymer with a high molecular weight (Mw> 100,000 g/mol), with high lactide conversion (> 95%), is obtained.3,6,28,29
Scheme 1. Synthesis of poly(lactic acid) catalyzed by tin(II) octoate.
O
O
n/2
O
O
Oct2Sn
H
O
O
H
O n 1
2
The use of tin (II)30,31 as a catalyst disqualifies the resulting material from some applications. In the case of contact with food, the content of tin (II) compounds should not exceed 1%. In biomedical applications, the product should not contain more than 20 ppm of tin.32 Such rigorous requirements concerning PLA for biomedical applications are the reason for the constant search for new biocompatible lactide ring opening polymerisation catalysts.33-36 Attempts are being made to replace tin compounds with catalysts of complex structure, containing aluminium,37-41 indium,42 lanthanum,43-46 or rare-earth metals.42.47 However, these metals are not considered biocompatible, as they do not occur naturally in the metabolic pathways of living organisms. Their use in lactide polymerization catalysts forces a very tedious and expensive process of purification of the polymer from the metal residue.4 In the PLA synthesis for biomedical applications, catalysts containing zirconium48 and titanium49-51 are used. It is believed that since these metals are used for the production of bone implants, due to their very low content in PLA, they will not adversely affect the body. However, these metals also do not occur in the metabolic pathways, so they are not biocompatible, and they are expensive. The use of a very expensive catalyst increases the total cost of polymer production. Due to the nontoxicity, the hope is placed in natural catalysts like creatine,52 or guanidine derivatives,53,54
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Organic Process Research & Development
however, the polymerization products often are dark in colour and their molecular weight is below 30,000. Over the past 10 years, a possibility of obtaining PLA enzymatically55 with lipasecatalyzed synthesis,56-59 e.g. with lipase from Candida antarctica60 or PS lipase (Pseudomonas fluorescens),61 has come to light. Thus obtained product had a very low molecular weight (
