synthesis of polylactides, polyglycolides and their copolymers

Clinical Materials IO (1992) 59-67

Synthesis of Polylactides, Polyglycolides and Their Copiolymers

Jan Nkuwenhuis PURAC -Biochern b.v., Arkelsedijk 46, PO Box 21, 4200 AA GORINCHEM, The Netherlands

Abstract: An overview is given of several polymerization routes of lactides and glycolides. Well-known in the literature are melt- and bulk-polymerization. These two polymerization types are discussed, showing that they have certain advantages and disadvantages.

Less known are the solution and suspension polymerization of lactides and glycolides. These two techniques are described in detail. In certain cases these polymerizations have advantages over the aforementioned ones.

It is shown that lower system viscosity enables better heat transfer during the reaction, resulting in a better, controllable reaction. The first results of solution and suspension polymerization are presented, showing that these techniques have great potential in the future.

INTRODUCTION

During the last decade polylactides and polyglycolides, including their copolymers, have received special interest because of their potential and proven use in the medical and pharmaceutical field. Especially in the field of wound closure, orthopaedics and controlled drug release, applications are well known and new applications are being develope:d. ‘-lo

In the early 1950s lactide and glycolide polymerizations were studied in medical and chemical companies like American Cyanamid (Wayne, NJ, USA), Johnson and Johnson (New Brunswick, NJ, USA) and DuPont de Nemours (Wilmington, DE, USA).11~~14 Extensive research led to the first commercial products in the early 1970s.

First, Davis and Geck (Stamford, CT, USA) (an American Cyanamid company) introduced their, still well known, Dexon@ sutures. Several years later Ethicon Inc. (Sommerville, NJ, USA) (a Johnson and Johnson company) followed with its Vicryl@ suture. The first one, Dexon@, is a suture based on a homopolymer of polyglycolide ; the second one, Vicryl@, is bassed on a copolymer of about 90% glycolide and HO % L-lactide.15-17

In the late 1970s and early 1980s other products were developed and introduced to the market, including products based on other Idegrading polymers like polydioxanone (PDS@ by Johnson and Johnson) or Maxon@ (a copolymer consisting of glycolide and trimethylenecarbonate). Quite re- cently the first products in the orthopaedic field became known; for instance, Biofix? by Bioscience Oy (Tampere, Finland), a series of PGA-PLA- based pins and products, and the Orthosorb@- or Ethi-pins@ by Johnson and Johnson”

In both cases the pins are used for the repair of small bone fractures. Other new products, based on the existing basic suture materials, have been introduced but also new companies are entering the field of wound closure; for instance, Japan Medical Supply (Tokyo, Japan) introduced a suture for the

Hydr.acid monomer m.p.

L-lactic acid L-lactide 97-98 D-lactic acid D-lactide 97-98 Rat lactic acid D,L-lactide 43-46

D,D-L,L lactide 123-125 Glycolic acid Glycolide 83-86

Fig. 1. a-Hydroxy-acid, corresponding monomer and melting points.

59 Clinical Materials 0267-6605/92/$05.00 0 1992 Elsevier Science Publishers Ltd, England

60 Jan Nieuwenhuis

Japanese market that resembles the existing Dexon@ products of Davis and Geck (American Cyanamid Company). It is expected that in the coming years several new applications will be commercialized and that the process of diversification will continue.

For the different application areas, basic materials are of prime importance, together with the tech- nology to form implants or other forms. For instance, in the orthopaedic field, mechanical properties and design (which of course are closely related) of the end product will be essential; to a lesser extent this will be the case in the pharmaceutical field, and so less attention needs to be paid to these aspects.

In this paper, an overview is given of the known types of polymerization, starting with a short introduction about the monomer types that are used for the polymerizations. The normal route of monomer preparation will be presented. The most common type of polymerization, which is used to synthesize the basic materials for suture production, is usually a kind of combination of the so-called bulk-polymerization and melt-polymerization. In this paper, these two polymerization types are discussed, and it is useful to define them. With bulk- polymerization, the reaction temperature is between the melting temperature of the monomers used and the melting or softening point of the resulting polymer. Usually this type of polymerization is carried out at temperatures slightly above the melting point of the monomers, resulting in a solidification of the bulk of the material at an early stage of the reaction. 10,18-22 In the case of the above-mentioned production of basic materials for suture production, a much higher temperature is used, enabling the reaction mass always to be, in general, in a highly viscous form. After a certain period of time, the temperature of the reacting mixture is raised to a temperature higher than the melting temperature of the resulting polymer: in this case the bulk-polymerization has become a melt-polymerization.

In general, melt-polymerization is conducted at temperatures higher than the melting point or softening point of the resulting polymer.

Less known are the solution polymerization and suspension polymerization of the monomers, the former being a polymerization in which the monomers are dissolved in an inert solvent together with a suitable catalyst and during reaction the polymer will, in general, stay in solution.

This type of polymerization is known in the literature,23-“2 especially papers concerning the

Glycolic - / iactjc %ci

Poiycondensatbx

Ring closure

Csude onomers

Distillation icrystallization

Purifie onomers Fig. 2. Simplified flow scheme of the mcmcmer productkm.

molten monomer is suspended or non-solvent, after which initiator is

variety of small bnlk-polymerizations reacting at the same time3”~“’

Early results of both the solution an polymerization will be discussed in this papx.

HE MONOMER

from five different

racemic mixture of D,D- an

D,D-r,,L-lactide from the fermentation- and L-lactic acid. In Fig. 2 the typic

are present.

weight polymers are obtained by t ization method.

Synthesis of polylactides, polyglycolides and their copolymers 61

In a second step the low molecular weight polymer is heated under a high vacuum and in presence of a suitable catalyst to give the crude monomers. This process is usually referred to as ring-closure. Several purification steps (crystallization/distillation) are used to give high- purity monomers for use in polymerization. One of the most important criteria regarding the monomers is their free acid content, as will be seen later, when bulk-polymerization is discussed.

Essential to the whole process is that the monomers do not contain water and are not able to generate water as a reaction product during reaction to high molecular weight compounds.

MELT-POLYMERIZATION

It is not’ed tha.t in the early 1950s lactide and glycolide polymerizations were performed at some large American companies. These polymerizations were performed at high temperatures and resulted in polymers of medium molecular weight. In many cases a combination of bulk- and melt- polymerization was used for these purposes.

The following procedure describes this method of polymerization. A reactor is filled with the monomer and initiator and co-reagents, after which the temperature is riaised to far above the melting point of the monomer or monomer mixture.

The first stage is usually a type of bulk- polymerization, meaning that the temperature of polymerization is below the melting temperature of the resulting end product or below the softening point of the resulting polymer (in the case of highly amorphous polymers). In general, the viscosity of the polymerization mixture is very high, but it is still possible to stir the reaction mixture. When the viscosity (of the reaction mixture becomes too high, the temperature is raised to a polymerization temperature higher than that of the resulting polymers., thus entering the field of melt- polymerization.

For small-scale production, raising the temperature is not always necessary : the polymerizations are fully performed as a type of bulk-polymerization. This is only possible on a small scale because of the poor heat transfer. During reaction the polymer mixture solidifies or crystallizes. Of course, stirring is not possible any more when this stage is reached. On a larger scale, temperatures have to lbecome higher to enable stirring of the reaction mixture, thus enabling a good heat transfer. In gleneral, temperatures ranging from 14s

5

230 “C are used during this type: of polymerization.

The resulting polymers are, in general, light- yellowish to deeper brown polymerls which can be used for the production of fibres. Tlhe yellowish or darker colours stem from degradation products which are produced during the reaction. The intrinsic viscosities (IVs) of the resulting polymers range from 1 to about 2.5, enabling the polymers to be used in common spinning and processing equipment.

The reason for the low/medium molecular weights that are produced stems from two processes. One is that at higher temperatures the reaction tends to go to lower molecular weight polymers ; at a high enough temperature, no polymerization occurs due to degradation reactioas. The other reason is that co-reagents are introduced to the reaction mixture which slow dow:n the reaction and/or lower the resulting molecu1a.r weight.ll-l7

For instance, when melt-polymerization is performed with the use of stannous octoate catalyst, depolymerization occurs at any stage of the reaction, and is an equilibrium reaction. At higher temperatures, the equilibrium tends to got towards the side of the monomers. It is known from patent literature that in these cases, and with temperatures up to 180 “C, 5-10 wt % monomer can be present in the resulting polymer.20s 21

BULK-POLYMERIZAT:[ON

As explained, the so-called bulk-polymerization is the type in which polymerizations are performed at temperatures lower than the melting temperature of the resulting polymer. This type of polymerization has the advantage that very high molecular weights can be obtained, provided that the temperature of polymerization and reaction conditions are well chosen. There are more advantalges with this polymerization form, one of which is the fact that less degradation products are produced during polymerization. A disadvantage is the end form in which the polymer is produced. Because the polymer crystallizes/solidifies during the reaction, the resulting polymer always takes the shape of the reactor in which it is produced. US Patent nos 4539981 and 4550449 describe the method in more detail, the method developed at lthe State University of Groningen being comparable to the methods described.lOT1*, lg

On a relatively small scale the method is simple ; the processing and purification oif the resulting

ECM 10

62 Jan Nieuwenhuis

(4 Temperature effect buik polymerization

a Temperature

polymerization cyilndrical

shape

Tsurr Radius

Temperature effect bulk polymerlzatlon

shape

Tpol

Tsurr. Radrus

Fig. 3. Schematic representation of (a) the effect of radius on temperature and consequently (b) the effect on molecular weight. (Tpol = temperature of polymerization; Tsurr = tem-

perature of surroundings).

polymer can be done by common methods. On a larger scale the processing and purification of the resulting block-polymer is troublesome. One can imagine that in cases where batches of 10~100 kg are produced, handling and processing of blocks of this size are not easy. This was not the only problem, as will be shown later.

At the State University of Groningen (Prof. Pennings’ group) the method of bulk-polymerization was studied in more detail. For instance, Leenslag and coworkers lg found that bulk-polymerizations performed at fairly low temperatures produced high molecular weight poly-L-lactide with a highly porous texture, giving the material special mechanical properties, such as an improved impact strength, indicating favourable applications in the orthopaedic field.

It was reported by the same group that there was a relationship between polymerization temperature, heat of fusion (indicative of the crystallinity of the material), molecular weight and yield of the polymerization. Among the conclusions was one concerning the ceiling temperature, the temperature above which no polymerization will occur or, in other words, no polymer will be formed. This

Not ~~vealcd in dence and conce

evolved from t

eat generation in a certain

The figure represen cylindrical reactor.

heat cannot be lremoved due tc the poor heat

transfer. Under normaI conditions the tern increase can be as this ~~~~~~~~;~~~

ing of the interior is and side reactions. 413


T

I.V. versus Free acid PLLA

7c- -+- i.v. 0 .z 6 :: .” 5 >

24 t! It\ a, 3 r f2

+1+,

1 +-+-------+_+

-/ I I I I 0 5 10 15 20 25

Free acid content (meqlkg monomer)

Fig. 4. IV (inherent viscosity) versus free acid content for PLLA.

of glycolide these effects are even more profound for several reasons. In the patent literature it is stated that, in case of the use of stannous octoate catalyst, the catalyst is fully compatible/soluble with the molten monomer :34 this is only partly true. It was found that this catalyst is only soluble in the molten glycolide monomer for temperatures from about 125135 ‘C. This means that polymerization of this monomer at temperatures frequently reported for the polymerization of Pactides, 105/ 125 “C, cannot be used in this case. Homopolymers of glycolide can only be made with the use of the aforementioned initiator from temperatures of about 130 “C, indicating that the reaction rate is higher than in lactide polymerizations performed at lower polymerization temperatures. Together with the fact that glycolide reactions are more exothermic than the corresponding lactide reactions, the con- clusion can be made that glycolide reactions are more diflbcult to perform. For instance, even at batch sizes of 2&30 grams, the normal polyglycolides produced have interiors with many exotic colours, stemming from degradation products.

The efIect of purity of the monomers can be seen in Fig. 4. The purity of the monomers is of importance for the end result of the polymerization. In this graph the effect of free acid content on the molecular weight of the resulting polymer is depicted. As can be seen, this effect is tremendous. In the cas’e of using monomers with a relatively high acid content, the above-mentioned processes are less profound.

Mixing of the monomers with free acids thus provides a tool for the control of the reaction.

From an industrial point of view these phenom- ena, together with the reactor form the polymer is produced in, require special design, reaction con-

ditions and consequently, downstream processing of the resulting materials

SOLUTION POLYMERIZ.ATION

The two aforementioned polymerization techniques have advantages and disadvantages. The advantages of bulk-polymerization are the high molecular weights that can be produced without severe degradation products ; the disadvantage is the heat generation during the synthesis and consequently the problems that come with large-scale synthesis. The advantages of melt-polymerization are the simple procedures; the disadvantages are the limited range of molecular weights that can be produced and the presence of degradation products in the resulting polymer.

There are two types of polymerization that could prevent part of the problems that are encountered with the aforementioned types of polymerization. These are solution polymerization and suspension polymerization.

Essential in solution polymerization is the relatively low monomer concentration c’ompared to the bulk- and melt-polymerization. Consequently, lower viscosities, and thus better he:at transfer due to the possibility of mixing during reaction, are present and the problems due to the exothermic reaction are prevented. Because of the better- controlled synthesis, the reproducibility of the reaction is better, another important criterion to consider in polymerization. Another aspect of this type of polymerization is that large batches can be easily made. Of course, as with the other polymerization procedures, disadvantages are present too. For instance, it involves the use of solvents which have to be removed from the polymer at a later stage.

In the literature little is known about solution polymerization. Some studies have been made, and usually the objective of these studies is to elucidate polymerization mechanisms or to Istudy potential catalysts or the effectiveness of several catalysts/ initiators. For instance, polycaprolactone and gamma-butyrolactone are frequently subjected to studies of this kind. In general, very high initiator concentrations are used for these plolymerizations, resulting in fairly low molecular weights. In most cases the resulting polymers are not useful in any application. A variety of initiators is used in the publications. In general, metal-alkoxides and car- boxylates are used. The resulting polymers always have IVs in the order of magnitude of about 0.1-0.5.

s-2

54 Jan Nieuwenhuis

No studies are known in which very high monomer- to-initiator ratios are used.

Solution polymerization can have advantages if certain polymers are required. In particular, crys- talline polymers of fairly high molecular weights can be made by this method. Starting with the aforementioned information from literature and with the information given earlier, we planned a set of experiments several years ago. The starting point was that we were only restricted in the use of a solvent, which had to be a common solvent, and that the reaction conditions should be simple. Surprisingly, the first results indicated that it was possible to make fairly high molecular weights wit this method: this was in contradiction with the general idea that it is impossible to make higher molecular weight materials with solution polymerization.

It was found that molecular weights up to two times the molecular weights that are usually produced with melt-polymerization could be obtained. Besides the high molecular weights, the reproducibility of the polymerizations were in good agreement with what we expected, that is, a highly reproducible method. Another advantage was the downstream processing of the material; after polymerization is completed it is very easy to purify and dry the material. Unlike the results from the literature we were able to get yields ranging from 96-100 %.

Figure 5 gives the results of two experiments we performed under the same polymerization conditions. Figure 5(a) gives yields and Fig. 5(b) the molecular weight determined by viscosity measurements. The curves show that a conversion of SO-90 % is achieved at an early stage of the reaction, indicating a strong influence of monomer concentration. Other experiments indeed proved that these reactions are first order in monomer concentrations.3”

After completion of the polymerization reaction, the polymer solution is cooled down and the polymer crystallizes from the reaction mixture. Separation of the polymer from the solvent is done by common methods, as well as the purification and drying of the polymer. The fact that crystallization is used gives one of the drawbacks of the system: only polymers that are able to crystallize from common solvents can be used with this method. It is difficult to make copolymers with this method without the use of other solvents or non-solvents (processes like precipitation from a solution).

Figure 6 gives some of the properties of the

Yield ver*us Polymerization time solutvon polymerization

<aI ‘/&

~~~~~~~~&+--~~~

,f --A-- 13/118a

8 -i- 13/1181:

20 I/ /

jB I I -__L_-_1 0 5 10 15 20 25

Time Ch>

Molecular weight versus Polymerizatron time

IOOr solution polymerization

ii /

a 40 --A-- 13/118a a,

f 20 -+- 13/118b

I I I ,

5 10 15 20 -2

Time 04

Fig. 5. (a) Yieid versus polymerization time; (b) molecuiar weight versus polymerization time measurements ; molecular

weight determined by viscosity (solution ~~~y~~~izat~o~)~

G.F.C. WV OR -----1

131118b 201000

Fig. 6. G.P.C., M.V. and or@ data of experiments 13/118a- 13/l 1% (see Fig. 5(a) and (b), (MV = mdecular weight

determined by viscosity measurement; D =

the re~rod~cib~~ity is


I I I I I I I I I 30 50 70 90 110 130 150 170 190 210

Temperature V’C)

20 @) Peak=177472

il

oLL---- ’ I I I I I I I 10 30 50 70 90 110 130 150 170 190 210

Temperature (“C) Fig. 7. (a) Solution polymerized poly-L-lactide as synthesized;

(b) solution polymerized poly-L-lactide after extrusion.

octoate is used as an initiator. This initiator is believe to polymerize the monomer by a coordination-insertion mechanism, whereas, for instance, metal-alkoxides initiate or catalyse the reactions by an anionic- or cationic-coordination mechanism. In the latter case, racemization is possible. One of the interesting points that can be seen from the table is the melting behaviour that is exhibited by the polymers. As can be seen from Fig. 6, the melting range of the polymers is very broad, starting to melt as early as 165 “C.

Figure 7 gives a possible explanation for this very broad melting range. Figure 7(a) is a thermogram of dried and crystallized material; Fig. 7(b) is that of the extruded polymer. It can be seen from these that the normal polymer produced has two endothermic melting peaks, whereas in the extruded material there is only one peak. At first we gave two possible explanations for, this phenomenon :

(I> something happens during polymerization ; (2) something happens during crystallization.

There is evidence for the second explanation. The first indication was the above-mentioned extrusion test. GPC analysis before and after extrusion showed a uniform molecular weight distribution, indicating that no two different molecular weights are produced during polymerization.. This was one of the explanations for the two-peak melting endothermic peak in DSC.

SUSPENSION POLYMERIZATION

In the early 1960s lactide and glycolide polymers were synthesized by means of a type of suspension polymerization.

This polymerization technique is usually a process in which a water-insoluble monomer is dispersed or suspended in water to give small droplets of the suspended monomer. Droplet sizes may vary from tenths of a micron to hundreds of microns. Usually, the suspension is stabilized by meclhanical stirring and with the addition of a stabilizer, a macro- molecular substance such as polyvinylalcohol. The stabilizer protects the formed droplet by creating a very thin layer of molecules around the droplet. During polymerization it prevents the individual droplets from forming aggregates. Aggregates can be formed during polymerization because of the increasing viscosity: at a certain stage the polymer becomes sticky and aggregation will occur. The process is initiated/catalysed by monomer-soluble catalysts and initiators. This means that the system can be considered as a series of bulk- polymerizations, where polymerization takes place at the same time and under the same reaction conditions. Because nothing happens in the con- tinuous phase, the viscosity in the whole system is constant. Again, the low viscosity during polymerization enables a very good heat transfer.

British Patents 825.335 and 932.382 describe a type of suspension polymerization of glycolide and lactide in a non-water system. In a series of experiments different gasolines were used, which have, of course, a negative aspect: their highly explosive character. The polymerization system was stablized by silicone-oil. The results were not that good in that low molecular weight polymers were synthesized. This was not in accordance with what should be expected when the results of bulk- polymerization were compared with their results. This indicates that something unknown influenced the reaction. The origin is difficult to trace; it might have been the quality of the monomers used or

66 Jan Nieuwenhuis

something present in the stabilizer could have influenced the reaction.

At CCA we did some suspension polymerization experiments with a comparable system used by the two authors and we also checked some other non-solvent systems. We used a one-litre reaction flask, equipped with conventional stirrer, nitrogen inlet and a refluxer. Initially, the system gasoil-L- lactide-stannous octoate was used at normal reaction conditions. Temperatures ranged from 8& 160 “C, reaction times from a few hours to 2%30 h. After the reaction was completed the system was allowed to cool to room temperature, after which the polymer was separated from the non-solvent.

The resulting polymers were quite easy to process and dry and what was surprising to us, molecular weights up to 175000 (determined by viscosity measurements) were obtained. Also surprising was the final appearance of the polymer after cation and drying of the polymer.

It was expected that globular forms would be found, and indeed they were. The globules are very porous, and, what is even more interesting, have a highly porous outside, which was not expected. This high porosity is caused by the crysta the formed polymer during the reaction. the round forms of the resulting polymer the dried material behaves in a fluid-like manner, making feeding to extrusion and molding equipment, for instance, quite easy.

This method seems to e one of the most convenient ways to synthesize these kinds of polymer, including the whole variety of homopolymers and copolymers. A limitation, until now, is the molecular weight that can be achieved.

It is expected that optimization of the suspension polymerization will eventually result in higher molecular weights. The procedu reactor, separating the resulting reaction is completed, and subsequent washing and drying of the polymer, is the easiest way of making these types of polymer.

CONCLUSIONS

Figure 8 gives an overview of the discussed four methods of polymerization with their advantages (+ ) and disadvantages (- >.

Bulk-polymerization performed at low temperatures is the only way at this moment to produce very high molecular weight polymers. For certain applications it might be the only polymeric material

1

I /

/__--_-__ t ____._-1-.-- .-.. _A I

Fig. 8. A~vantagesl~is~~va~tages of the several methods. COP: cop0 ; LS: large scale ; final-.

form end product.

that can be used. There are so

cult and expensive to make very iarge

era11 the simplest of e only ~~str~~t~~~ is

1.

2.

3.

4.

5.

6.

7.


Pizov, (G. & Uretzky, G., Biomat, Art. Cells, Art. Org., 16 23. Kricheldorf, H. R. & Kreiser, .I., Makromol Chem., 188 (4) (1988) 705sI9. (1987) 1861-73.

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synthesis of polylactides, polyglycolides and their copolymers

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