SA91120200B1 - Preparation and purification of POYLACTIDE - Google Patents

Abstract

Abstract: Polylactide in a pure state fulfills the following requirements:- It fulfills the required color strength requirements according to the reference solutions B2 - B9 of brown color registered in the Encyclopedia of European Medicines Pharmacopoeia, second edition (1980 AD), part one, chapter 2:6. It contains one or more metals in cationic form, and the metal ions do not exceed a concentration of 10 parts per million. Polylactide is particularly suitable for use as microparticles or for an implant and preferably contains a hydrophilic drug such as octreotide or a lipophilic drug such as bromocriptine.

Description

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Preparation and purification of polylactide Full description Background of the invention: _polylactide This invention relates to a method for purifying, for example, polylactides 177095417 European patent No. 177095417 describes glycolic acid and lactic acid prepared by condensation Polylactides-co-glycolides a with £ in the presence of lactide and glycolide polymerisation via a polymerization route oe Jai or ° Ben Load, tin di- (2-ethyl hexanoate) catalyst for example Example: .tin octanoate or tin octoate by dissolving it in an insoluble or soluble solvent of polylactides repelled, then washing the solution with a partially water-soluble methylene solution such as an aqueous acid such as 110 or a preparation for the gastric ion hook. 0 and thus turns the metallic catebone . EDTA as a metal ion compelling agent from it to the aqueous solution complex or catalyst metal cation catalyst; whose solubility is better. /i In general; It is after separating and isolating the organic solvent layer “B” from it, for example, by mixing the layer with an organic solvent, polylactide, and precipitating Yo — which dissociates “methanol, such as alcohol, or alcohol, Petrol ether, such as the precipitate, containing an amount of polylactide from the solution and the polylactide remains about ¥ part of a specific catalyst metal cation of the catalyst metal cation eg in catalyst anion per million - in addition to the catalyst anion specific AS on the polylactide acidic form; in addition; contains

Z. pg From secondary tissues resulting from decomposition and brown color, elt is formed. The polymer processing process, la gua polymer, is under the influence of a catalyst. Z Given that Jai polylactide-co-glycolides J— is polylactides, they can be used as containers, matrices for drug compounds, as is the case in ° vaccinations, implants, and microparticles that are given by injection. Residual impurities can cause local irritant reactions to body tissues and can also cause, for example, instability of sal, depending on the type of catalyst, and thus may lead to rapid dissolution and absorption of the drug. Therefore, it is preferable to remove the brown and catalytic impurities as well as possible. | Catalyst-free polylactides produced from acid condensation 18600 and Cn glycolic acid of choice are known but have molecular weights mde ranging from FI PUD to 4000. Higher molecular weight polylactides are preferred and cannot Manufactured only in the presence of a catalyst. 0 according to European Patent No. 1: Lactic acid and glycolic acid were reacted in the presence of a strong acidic ion-exchange resin as a catalyst, which can be removed after the reaction from the copolymer product by filtering a mixture! the reactants or cool them down and then dissolve the copolymer in an organic solvent in which the ion-exchange siresin is insoluble; Followed by filtering the solution and removing the organic solvent and then obtaining a copolymer. The catalytic precipitate aie was removed to a high degree. In this way, only Joma was made on polylactides with a molecular weight ranging from about 0001 to 001 o. : a

lb: X 4 Nim 101718011065 Mkl polyletide-co-glycolides with a wide range of Ht in terms of molecular weight reaching about 70.8 and it is preferable to use 68 ° with Ste 17006 as polymerization units of monomers «but it is its copolymerization in the presence of a metal catalyst; Which is the type of its reaction as °Lal was discussed, which leads to the presence of impurities in the form of Lysl in the reaction product. A general description of the invention: A. We have now discovered that it is possible to obtain polylactides hydrolyzed with polylactide-co-glycolides, especially those prepared from the reactions of lactide glycolide monomers 0. We say that they can be obtained in a form of better purity. The invention provides a method for obtaining a polylactide: an ester of ester 028 alcohol containing at least three Lh nS hydroxyl groups and being pure and meeting the following requirements: - Yo - color strength of reference solutions By-By Structure as measured by color in: European Pharmacopoeia ¢ second edition (1380 AD); Part (0) J CN chapter - contains one or more metals in cataionic form “1g” and the metal ions do not exceed a concentration of 01 parts per million. impure polylactide with the surface of a matrix container containing carboxylic groups, then the pure polylactide was isolated from the secretion.

It is preferred that the polylactide has a low color strength compared to the reference solutions and 134-13, especially the reference solution, By. The color of the Bo reference solution indicates that the polylactide is gray off-white or colorless. The polylactides, which are particularly preferred to be processed, contain divalent metal ions such as lead 207, especially tin (Sn). To determine the amount of tin, the polymer is analyzed under high pressure with a mixture of hydrochloric acid and nitric lighter. Tin is deposited and concentrated from the mixture on a filter membrane and metal quantification is measured by energy dispersive X-ray fluorescence (EDXRF) as described by B-Schreiber H.R.

Lindner, HD.

Seltner ial » International Journal of Analytical Environmental Chemistry; 1441 A.D. Vol. (01) p. (VY-17) provided with a reference to the graphite furnace atomic absorption spectrometry method as documented in: Seltner, H.D; Lindner, H.R; Schreiber, 3. Intern.

J.

Environment.

Anal.

Chem. , Vo Vol. 10, p. 7-12. Colloquim Atomspektrometrische Spurenanalytik, 1981 | : 60 - th April, 1991 in Konstanz, Germany, Authors: H.

Seltner, 8-12 - Hermann and C. Heppler. : | .© - / 0 according to the invention; The concentration of 80 in the Polylactide related to the invention 0 is preferably 0, ppm at most and at most) ppm ¢ It is preferable that the catalytic anion be ethyl-hexanoate : whose concentration does not exceed 70.5 at greater than the weight of the pure polylactide of the present invention. : the mom

+ In addition to the M1800 units present in the purified polylactide, it is preferable that it contains other structural units, for example, similar to those described in the European patent application No.: 177044897, second paragraph, fourth page; The led glycolide unit is the preferred unit °, because it is according to the ratio of monomer in the polymer chain pli a to reduce the time of decomposition of the polymer in the body and then Slay the drug compound. The glycolide unit, as it is known, is the most widely used additive unit in -polylactides. According to the invention, the ratio of molecular monomers is preferably 0 to units of Yo — 001 glycolide [lactide / sf-Vo] and in particular Yo — vo Yo — Yo and especially 0 _ 1 / £0 — To more specifically oo — 0{ / 5 — 00 For example, oe —t0 [o. —o00 Jal ‎$i) Cia gl) for more details:: | It is known that the polymerization reaction of monomers such as glycolide slactide 10 is fractionated preferentially in the presence of a compound containing: one or more hydroxyl groups which act as ; As a starter to form a linear polymer chain. actually ; These prefixes are used to control the length of the polylactides chain. The well-known initiators contain lactic acid + and glycolide acid, and other compounds containing Jia hydroxyl groups can be used. A small amount of the starting hydroxyl compound can lead to the formation of longer chains than in the case of using large quantities. Superior regulators are those polyols described in Cle Application No. 700477 for which glucose (5—S slall 5 mannitol Lg) is preferred in particular. . z 0 z roy

Not by using this type of compound starting it can be obtained

It contains materials with a molecular weight, Me, of Polylactide-co-glycolide, which are very suitable as grafting materials or microparticles and contain ? or ? Preferably greater than? (4) (te) short chains of polylactide-co-glycolide

M and can be dissolved in the tissues of the body within a short period of release of the drug and the paragraph reaches a few weeks (for example, two months or more) and preferably during; - 1 months (0 months, for example). Although, according to the present invention, pure polylactides may have a linear composition ¢, the pure polylactides ke of the invention are those which have the composition described in the British patent

0 No: 17 0 which are esters of polyl containing ? Hydroxyl groups of at least 0 and it is preferred that Jad jiu sugar ester of sugar or Su sugar alcohol, especially al

glucose 0. glucase ester, which is a star-shaped structure with a center of 0

The rest of the glucose and rays are represented by linear polylactide chains.

yo After processing the polymers, the asterisks are more than

Z polymers are linear and become tinged with brown by-products 6 200

Because the sugar or sugar alcohol used in its preparation. It may also have been partially eroded by the action of the bat. The "sr polymers" contain ratios of glycolide / lactide molecular units that preferably

linear polymers are those referred to above for linear polymers »0

Star polymers are preferably of medium molecular weight

Yer Gall Yen dees one M,

0, specifically between 8000© to 10,000, for example, about 50,000, and it is preferable to have a physical property, polydipersity, 1/0/4 between 117 to Veo, specifically between Yor to 0 for "oo" lam

"M

8 . It is preferable that the polylactide-co-glycolides of linear structure Al do not represent star polymers in their pure state (Lah) of the invention having a medium molecular weight between Yor to : 0 and it is preferable that they contain MUM, polydispersity between 011 to .1

° Molecular weight is determined using gelpermeation chromatography and they are polystyrene as the reference material for Nie measurement The column contains 1000 Dupont ultrastyragel R to be al

tetrahydrofurone. According to the invention it is possible to obtain polylactides cleaved in a new way by combining a solution of impure polylactide with activated charcoal

active charcoal 00 and isolate pure polylactide from the mixture. This method is also part of the invention.

This method is known from British Patent No.: 153179110 and patent

European number: 1181371 for the treatment of polymers produced in the presence of a catalyst with activated charcoal. .

According to British Patent No. 1654979470, polymer is a term

/ or propylene oxide “ethylene oxide” such as alkylene oxide obtained from polyether

3 Contains a compound active hydrogen with active hydrogen epichlorohydrin in the presence of a primary catalyst. The polymer sucrose or sorbitol »glycerol reduced dsl is purified to remove magnesium silicate with a mixture of active polymer charcoal

Polyethylene glycol as polyalkene glycol from polyethylene glycol vy, dark-appearing polymers formed as by-products that give the polymers inadequate as well as chemical properties. In a preferred method; viscosity and viscosity | 2 By a method that we have not put poly ethers, a pre-treatment of the . ) page 2, lines 16-20) to remove the unreacted and catalytic alkylene oxides

z z no

q | Therefore, it is not possible to remove the primary catalyst with a mixture of charcoal and -magnesum-silicate according to European patent No. D. A solution of polyakyene ether is mixed in cyclic ether or a solvent polyoxytetramethylene glycol polyhydric alcohol ° equipped with a tetrahydrofuran of polymerisation under the influence of a catalyst of heteropoly acid such as 12-tungstophosphoric acid » this is mixed with an organic hydrocarbon or a halogenated hydrocarbon ¢ this solvent which contains the bulk of the Heteropoly acid is separated from the other phase and the residue is extended for purification Aah aay solid adsorbent Jia solide adsorbent vegetable charcoal 0 aluminum oxides or oxides ¢ hydroxides or carbonates such as Mg or Ca with basic ion exchange resin as per Table 1 No. 7; The polymers contain 0.7 to 1.8 ppm acid mineral impurities after being treated with activated charcoal. Vo, therefore, this purification process is used to purify polyether and remove laa grooved type from acidic catalyst and cannot be predicted in advance aly / charcoal can be used to remove 0 Sn Jia cations also cannot be predicted It is already established that these low impurity levels can be reached as 0 is indicated. . Tak 7 of the purification process of the invention; The quantities of activated charcoal used generally range from about 10 to 7700, for example, 10 to 1 of the weight of the polymer. Any available vegetable charcoal such as that described in the Pharmacopoeia may be used. Anorexia type model: Tabati is that of ‎-Norit of clydesdate co. Ltd. , Glasgow / Scotland z z z z z z z z z z z z z z z

Ye

ZNO Charcoal pulverizer is usually used as finely pulverized as suitable charcoal passes ¢ micrometer VO at least through an aperture sieve such as Norit as used in the following example described in the appendix and available from Norit ‎ "Summary of methods for testing Noritactivated carbons on specifications"by J. Visser. Of particular interest is the new method of purification with charcoal. Dark brown star oils © Polymers for polymers that are unstable “glucose” such as glucose polyol can be partially achieved by coloration with heat, especially in The presence of a catalyst and its color dominates the color of the paint 0 By The reference for the color It is believed that the presence of small amounts of acid groups in coal 1 If The active vegetable cations are responsible for the amazing removal of cations in an organic solvent assay: with charcoal catalyst The catalyst solution has been treated with vegetable as the catalyst compound is wetted and the tin removed with vegetable charcoal which is completely laid back in the catalyst anionic part The invention also provides a method for purifying the residual fic. For this purpose Js ladle ; impregnated with a system containing polymer in combination with a solution of the polymer, polylactide ; In gypsum polylactide on acidic groups on its surface and then isolate the os | - The purifier. It is possible - upon request - to use a weakly acidic cationic exchanger vy carboxylic acid with a carboxylic acid.

Cd is effective if it has a suitable small particle size. on the way; The hydrogen ionic wet scout is one of them with an ionic hydrogen form (Adal) about 14 / liter (apparent) and about 1.76 g / liter 0 shipping weight 190 g / liter; effective particle size “© to < 0 mm; mother content

blood humidity £Y to 787; allowable pH range 0 to 04 ; Maximum operating temperature 10 mm 0 Total exchange capacity 01 meq (dry) 0,¥ meq/ml (wet). An example of this is Amberlite IRC-50 Methacrylic aci DVB (available from Fluka, Switzerland), which is milled to a reduced diameter particle size, for example, less than 1 mm or 0 microns. It is preferable that the system contain For purification, such as charcoal, at an appropriate concentration ranging from 0.01 to (+) ml of acidic groups per gram of the system, and it is appropriate for it to be in the form of granules that can be reduced. The diameters of the grains are usually between 1 00 micrometers to 1 mm, for example between 100 — 100 micrometers, so they have a large surface area. On a JL filament the activated charcoal contains approximately 1,000 µL per millimeter of system material. The exploration process of the invention is preferably concerned with the preparation of a polylactide extension using glycolide lactide as monomers and metal cations such as 07 as a catalyst ¢ Given that this polymerization process gives better production and a higher molecular weight - upon request - than in the process / processing using polylactide acid and glycolic acid as starting compounds and resin. The strong acid with ion exchange as a catalyst ion exchange is described.; In EP No. 011694..z starting with doped polylactide-co-glylactide containing approximately 0 ppm SnT; The concentration of 50" can be reduced to about 10 ppm. The coal-fired purification process, CJA | father mother

l Reducing the Sn content, as already mentioned, to less than 1.0, for example, less than 1 ppm. It is preferable to perform the five-say purification process p with a solution of polylactide dissolved in acetone although other solvents can be used. The process can be followed up with another peptic process; It is preferable to be an ultrafiltration membrane filtration process that contains the contents of compounds with low molecular weight i, such as glycolide lactide. A polylactide solution can also be used in this process. After the second purification process; Purified polylactides with a monomer content of 0) can be obtained by weight from the polymer and preferably * 0.7 over the most from the polymer example 1,7 from lactide and P "7 of 0 glycolide, water content #1 at most; organic Cuda mL acetone methylene chloride; content (7) at most, preferably 74.0 at most, for example, 70 at most, and 71 ash content at most By weight, the polylactide is 0. It is preferable that their acid number be 01 at most 0. Therefore, the purified polylactides are preferred to be used through the gastrointestinal tract as |©" system for drug compounds, especially in vaccinations or in the form of microparticles . These images can be prepared by the traditional methods explained above in 1 European Application No.: 084481, British Patent Application No.: 711584577, Application: YL European Patent No.: 1001 and American Patent No.: 4187441 and: 2711787; And the French application No.: 74917801 and the American patent No. S and 14 4 / R / 0.

Z 'w z images are suitable, for example, to contain an absorbent drug el all with peptides such as cyclopeptide, specifically a peptide containing a jumping hormone such as somatostotin, specifically or octreotide or the addition of an acidic salt or Gi Ga from it or a drug J ergot alkaloid (Ji lipophilic drug bromocriptine . Pharmaceutical compounds are formed by mixing purified polylactide with a drug compound: for vaccination or body) 8 3 0 Example: 1 | 0 (i) Preparation of PLG-Glu This is prepared as described above in British Patent Application No. 0. L lactide polymerization is done, i and 01/40 (glycolide by weight) while containing di nd 1S of glycolic acid lactic acid glycolide lcatide as an impurity at 1171 C in the presence of 70.7 (W/W)© (+) glucose and 70.1 (W/W) 0 of tin octanoate ( Product Ty from Chemicals 1 8 14 is a tin salt: vo of 2-cthyl hexanoic acid; lemon yellow liquid with viscosity (oY ; 1 +; light reflectance index 1,458; tin content $Y - YY 0 content of 2-ethyl hexanoic acid according to the calibration of NaOH 14. The product is polylactide-co-glycolide glucose ester (PLG-Glu) containing a ratio of 50/101 glycolide / lactide g (bases) or £0/00 mole (bases). The color YL is Gale brown and the color is more intense according to the color coefficient used than in the reference solution By. Tin content 06 dm ppm. : z z m

0: ; b) Treatment with active charcoal. Dissolve 0 g of PLG-Glu in: 0.5 mL acetone to dissolve into a clear brown solution. Within minutes, activated charcoal is added. Mix the mixture for how long? hours at room temperature and then filtered. © The filter material is washed with 10.5 liters of acetone. The filter output of 0 is slightly yellower than the color coefficient, By . It is diluted from acetone by vacuum and the residue is dried at 6 m and finally subjected to a vacuum at 1 mm Hg and a molecular weight of Ore ; ZY glycolide / lactide content; alkyl metal content; Less than 1 01 ppm 1 Analysis yield: 1 788” ppm; 70 1 ppm Ni and Sn are each less than one ppm. The filter charcoal contains virtually all the tin CoE zai ll contains 2-ethyl hexanoic acid JS from the catalyst (if the experiment is repeated with +75 activated charcoal by weight of the polymer, 1 the product contains Ya. ppm of Sn ). c) Ultrafiltration The product of part (b) (+ VAs g) is dissolved in Hd 0.8 of acetone to give a bright yellow solution. The output is subjected to microfiltration using a laboratory pressure filtration apparatus ¢: vy. using acetone (approx. ; (alla YA Xx) as a solvent under pressure of #0 bar containing a membrane of type FS 81PP DDS (exception limit 1000) and diameter VE | z cm. With a permeation rate of about 110 to 115 milliliters / hour.contains solution, z z z z

1 0 yellow colored glycolide and lactic acid glycolide / lactide is applied to ml of the solution (after #7701 laa all) The remaining solution is evaporated in a room £1 hour has passed from the process. The result is taken Again in 8000008 gm is filtered onto VEA) m in a vacuum. The product contains Av — and dries at AA 7 +, Y acetone with TUI . glycolide by weight Z+, +0 lactide by weight of 70.1 0 gas chromatography upon detection of 2-ethyl hexanoic acid by weight. did not appear

GPC, i.e., its content is less than (70) molecular weight 5580060 according to (Drugs) of the European Pharmacopoeia (Dea) according to the subjected tongue test, it is considered polymer, second edition, chapter 4 77, the polymer is European Pharmacopoeia

By colorless . The result is not more intense in color than the reference 0 solution

HY) example of purified poly (D, L-lactide-co-glycolide) adsorbate; kg of kgbm of oy described in example ( \ ) and containing a molecular weight of 001 in 0.methyle chloride; was mixed into the filtered solution. bromocriptine mesylate was mixed in kg of 1 Vo 0 of the fine particles was added Jas and spray dried Ultra-Turrax-Ddaul 53. Fine particles were vacuumed into a £0 — £4 xc vacuum flasks (KGY Yo) under nitrogen and sterilized with gamma rays (dose © L).

The final product is two sterile syringe chambers (TCS) consisting of 8 parts containing clay all and one part containing all for fine particle suspension. Like | Potassium-dihydrogenphosphate Aha | |__Disodium-hydrogenphosphate (anhydrous) PluonicFe8 Yer |- Sodium-carboxymethylcellulose (Blanose 7LFD) | 'vr | Bemgylaleohol | Meee 0 mll water for injection por 1 nd: Meee quencher Nitrogen | 4s Ld. Injection (TCS) is suitable for example for intramuscular injection once every; weeks. Results from two-chamber clinical studies (TCS) show: for postpartum dysphoria ¢ patients with hyperprolactinemia; in the blood / macroprolactinomas ¢ and patients with tumors; 0 macroprolactinomas « never yd wa | The substance ab al " has a reasonable and regular ability to tolerate local pain in addition to good efficacy for single or multiple administration of bromocriptine ia 9 particles: dissolve 1 g of —u all 4335 ¢ poly (D,L,lactide) -co-glycolide ) glucose 1/50 ( 10 fees ) molar ) produced according to the method contained in 0 '° BR No.: 7145477; Calcium Polydisperse 1,7. Product of 70,7 vv

0 by weight of glucose glucose and purified according to example (1) in 10 milliliters of methylene chloride with magnetic mixing followed by the addition of VO mg of Octreotide dissolved in 1.177 milliliters of 0 methanol The group was mixed well eg by Ultra-Turax for 1 min at a rate of 0001 rpm Cus yielding a suspension of very small crystals of Octreotide in the polymer solution. The sled was sprayed with a high speed turbine, Niro Atomizer, and the small droplets were dried with warm air, giving off fine particles. Z fine particles were collected by 0 and dried overnight at room temperature in a lattice oven. Ya microparticles were washed with a physiological solution of 1 part acetate; pH equals; acetate for minutes and then dried again at room temperature in a lattice oven. The fine particles were sieved after VY processing (mesh sieve size 1171© gm) to obtain the final product. 0 z z z Vo The microparticles were suspended in a tank and given at the rate of | © mg / kg in J sail as a dose of Octreotide for white rabbits ; (chincilabastard) and subcutaneously in 01 mg / kg dose for male rats. Periodic blood samples were taken to clarify plasma levels with values of 0.1 to 01 ng/ml (mg ® dose) in rabbits and 0.5 to 1 ng/ml in rats. ?; Day as measured by Radioimmunoassay (RIA).

Claims (1)

VA | Claims 1-1 The method of obtaining a polylactide is an ester of a polyol containing Y at least three hydroxyl groups « and it is pure v and meets the following requirements : $ = strength of color according to reference solutions ‎B; - By brown color recorded in ° European Pharmacopoeia Encyclopedia «Second Edition q Ae (1 um) Part 1 Chapter E + 1: ? 3 7 - Contains one or more minerals in cationic form cationic form nor A | the metal don ion (ions) exceeds a concentration of 01 ppm 4 | - contacting an impure polylactide solution with the surface of a matrix container 1; containing carboxylic aggregates groups, and then isolated the pure polylactide 11 from the secretion. —F ) | method according to claim a) in which the isolated material includes further steps J Y of selection which is ultra-fine filtration “ls ultra filtration 1 +- method according to claim 1 to ©; in which the impure polylactide Y dissolved in .acetone: 1 0—method according to claim 1 to 4; in order to obtain a polylactide having Y color strength of the reference solution and 3 - 34. For the 1 +- method according to any of the claims 1 to 0 ; in order to obtain a polylactide Y of color strength for the reference solution Bo a | 1#- method according to any of Claims 1 to 6; In order to obtain polylactide Y in which metal ions are Sn" 1 +- method according to claims 1 to V; in order to obtain polylactide Y concentration 501 in it at most, + 1 ppm 0 4- A method according to any of the claims from 1 to A to obtain a polylactide with v salt anions is -ethyl hexanoate -01 1 method according to claim 4 in order to obtain a polylactide having a concentration of ethyl hexanoate at most 1.8 7 by weight of any polylactide -11 1 method according to For any of the claims 1 to 01 to obtain a polylactide for which: 1 | 7 of the weight of | contains the most | monomer polyhetiee | 1 | of the weight of . | contains the most | Ch polytectide water 71 | by weight of | contains the most | organic solvent z | # no m ed PORE ——— ; 1 | by weight of -2 contains the most | ash J | ash poli | lat a 1 0 by weight of the | contains the most “a and has an acid number 1 acid number a -10 1 method according to any claims 1 to 11 to obtain polylactide 0 containing more -1-glycolide events 1 method according to claim VY; To obtain a polylactide has a ratio: Y molarity of Yo - 001 glycolide / lactide / zero - Yo: the 1 4- method according to claim VV; To obtain a polylactide having a molar ratio of Y and L-Yo - Yo [Yo -1 1 method of claim 4; For a polylactide having a molar ratio =f [f= Y -11 1 method according to claim 1 ; To obtain a polylactide the Y ester of sugar is an ester of sugar or sugar alcohol sas Su. -17 1 | method according to claim V1; To obtain a polylactide the Y is a glucose ester. glucose ester —YA 1 method pursuant to claim 01 or 117 ¢ to obtain a polylactide of 7 with an average molecular weight of 11 to 11 Nea, enn 1 4- method according to protection element 11 or 117; For a polylactide that has a polydispersity of 1, the molecular weight/molecular weight spread is 14.04, the polydispersity of VY to .0. | that