Process for the preparation of copolyesters

Details Process for the preparation of copolyesters Process for the preparation of copolyesters

2000-02-15

2001-10-02

Acquah, Samuel A. (Department: 1711)

Synthetic resins or natural rubbers -- part of the class 520 ser

Synthetic resins

From carboxylic acid or derivative thereof

C528S357000, C528S358000, C528S361000, C528S403000, C528S409000, C528S410000, C524S779000, C524S783000, C524S785000, C524S788000

Reexamination Certificate

active

06297350

ABSTRACT:

The invention relates to a process for the preparation of copolyesters using cyclic esters as monomers and a metallic salt of the formula Me
2+
X
2
as catalyst.
Biologically degradable plastics such as polylactides or copolyesters of lactic acid with other hydroxycarboxylic acids are used to an increasing extent for medical and pharmaceutical purposes, for example as matrix materials for pharmaceutical active ingredients, as medical suture materials, as devices for setting bone fractures or as wound materials.
Amorphous polymers are generally preferred in the preparation of depot medicaments, since they exhibit a homogeneous degradation behaviour in the body and therefore ensure a uniform release of the active ingredient. Moreover, active ingredients can form deposits better in amorphous than in crystalline polymer regions.
Since homopolymers mostly have a semicrystalline structure, copolymers are preferred for the preparation of depot medicaments.
Gilding and Reed, Polymer 20 (1979) 1459, describe the preparation of copolyesters of glycolic and lactic acid using tin octoate as initiator. Tin octoate, however, allows only insufficient control of the polymerization reaction. Initially, the glycolide predominantly incorporated into the growing polymer chains due to the different reactivities of the monomers. Only when this is largely used up does a noteworthy incorporation of the lactide take place. As a consequence, block copolymers are obtained which tend to form crystalline regions. Moreover, the use of tin salts and other heavy metal salts in the preparation of polymers for medical purposes is problematical.
Kricheldorf et al., Makromol. Chem., Suppl. 12, 25-38 (1985) 25, investigate the copolymerization of glycolide with L,L-lactide and other lactones. In addition to tin salts, FeCl
3
, ZnCl
2
, ZnO, ZnS and zinc dust inter alia are used as initiators. Monomer and initiator are used in a ratio of 100:1. Here, too, only block copolymers were obtained when FeCl
3
, ZnCl
2
and ZnS were used. Only ZnO and zinc dust resulted in amorphous copolymers at temperatures of 150° C., but ZnO brings about a racemization of L-lactide and produces only relatively low molecular weights. After polymerization, zinc powder must be laboriously separated off in an additional purification step, and the molecular weights of the polymers can scarcely be controlled.
Bero et al., Makromol. Chem. 194 (1993), 907, and Kasperczyk and Bero, Makromol. Chem. 194 (1993), 913, disclose the copolymerization of L,L-lactide and E-caprolactone using inter alia ZnEtOiPr as initiator and chlorobenzene as solvent. The use of non-toxic solvents or solvent-free reactions are not described.
None of the processes known up to now allows the reproducible, controlled preparation of copolyesters with a random sequence. Moreover, the use of the named initiators is in some cases associated with serious disadvantages.
The object of the present invention is to provide a process which allows the reproducible preparation of copolyesters with a random sequence under controlled conditions.
This object was surprisingly achieved by polymerizing cyclic esters in the presence of a metallic salt according to the formula Me
2+
X
2
, in which Me
2+
represents Mg, Ca, Fe(II), Mn(II) or Zn, and X is an anion of an aminocarboxylic acid, hydroxycarboxylic acid or a halide, and in which monomer and catalyst are used in a monomer/catalyst ratio of greater than 100.
Preferred aminocarboxylic acids are aliphatic or aromatic, &agr;- or &ohgr;-aminocarboxylic acid such as 4-amino- and/or 4-(acetylamino)benzoic acid, saturated or unsaturated C
1
-C
18
acylaminobenzoic acid, particularly preferably C
2
-C
18
acylaminobenzoic acid with an even number of C atoms, in particular C
4
, C
6
, C
16
or C
18
acylaminobenzoic acid. Also preferred are &agr;- and &ohgr;-aminoalkanoic acids, particularly &agr;- and &ohgr;-amino-C
2
-C
6
-alkanoic acids or N-acyl, N-alkoxycarbonyl or oligopeptide derivatives thereof, acyl preferably having the meaning given above. Particularly suitable N-alkoxycarbonyl radicals are C
1
-C
18
, in particular C
1
-C
4
alkoxycarbonyl radicals, most preferred is ethoxycarbonyl. Preferred oligopeptide derivatives are dipeptide derivatives, in particular dipeptide derivatives of the amino acids glycine, alanine, sarcosine and proline.
Preferred hydroxycarboxylic acids are aliphatic or aromatic &agr;- or &ohgr;-hydroxycarboxylic acids such as glycolic acid, &bgr;-hydroxybutyric acid, &bgr;-hydroxyvaleric acid, lactic acid, mandelic acid, 4-hydroxybenzoic acid, salicylic acid and N-acetylsalicylic acid.
Preferred halides are chloride, bromide and iodide.
Me
2+
preferably represents Fe(II), Mn(II) or Zn, quite particularly preferably Zn.
X preferably represents lactate, mandelate, glycolate, bromide, iodide, particularly preferably lactate, bromide, quite particularly preferably lactate.
Particularly preferred catalysts are iron(II) lactate, manganese lactate, zinc lactate, zinc mandelate, zinc bromide and zinc iodide, in particular zinc bromide, zinc lactate and iron(II) lactate.
Two or more different monomers are used to prepare copolymers, preferably structurally different monomers being used, i.e. monomers which differ not only by virtue of their stereochemistry.
Suitable as monomers are in particular cyclic esters and cyclocarbonates. Preferred cyclic esters are dilactones, such as glycolide and lactides, as well as lactones and esters according to the formulae
in which m=0 to 4, preferably 1 to 2 and quite particularly preferably 2. The index n represents 2 to 12, preferably 2 to 6 and particularly preferably 2 to 4, and R represents H, CH
3
or C
2
H
5
.
Preferred lactides are L,L-lactide and the racemate of L,L-lactide and D,D-lactide. L,L-lactide is often also called L-lactide.
Lactones are inner esters of the hydroxycarboxylic acids. Preferred lactones are &bgr;-butyrolactone, &egr;-caprolactone, p-dioxanone and (L- or D,L)-&dgr;-valerolactone. Quite particularly preferred are &egr;-caprolactone and p-dioxanone.
Preferred cyclocarbonates are compounds according to the formula
in which p=1 to 8, preferably 1 or 2. R
1
and R
2
independently of one another represent H, straight-chain C
1
-C
6
alkyl or form, together with the carbon atom to which they are bound, a 5- or 6-membered Spiro ring.
Two different cyclic esters, in particular two different lactones and/or dilactones, or cyclocarbonates or a mixture of at least one cyclic ester and at least one cyclocarbonate are preferably reacted with one another.
Mixtures of lactide and glycolide, lactide and &egr;-caprolactone as well as lactide and trimethylene carbonate are preferred. Lactide and glycolide are preferably used in a molar ratio of 1:1 to 9:1, lactide and &egr;-caprolactone or lactide and trimethylene carbonate in a ratio of 9:1 to 1:9, in particular 9:1 to 1:1.
The polymerization is carried out primarily as a bulk polymerization, i.e. in the melt in the absence of solvents. Small amounts of an inert liquid such as e.g. paraffin oil or a siloxane, for example polydimethylsiloxane, can be added in order to improve heat transfer. The process according to the invention is preferably carried out in the absence of water.
The initiators can be used in the form of solutions in order to facilitate dosage. A preferred solvent is diethyl ether. Furthermore, it was found that, when ether solutions of the catalyst are used, polymers with higher molecular weights can be obtained. This process variant is particularly suitable when metal halides are used.
The polymerization temperature is preferably 40 to 250° C., particularly preferably 60 to 200° C. and quite particularly preferably 60 to 180° C. Most preferred is a temperature range from 100 to 160° C. The optimum reaction temperature for the system in question depends on the monomers used and on the catalyst used. For example in the case of mixtures of lactide and &egr;-caprolactone, a reaction temperature in the range from 100 to 150° C., in the case of mixtures of glycolide and lact

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