__________________________________________________________________________ mole weight & amp ; volume required moles ratio__________________________________________________________________________6 - apa 1 kgw ( kf = 0 . 02 %) 4 . 62 1 . 0mecl . sub . 2 ( methylene 20 l . ( sieve - dried ) as -- -- chloride needed . sup . ( 1 ) tea ( triethylamine ) 1 . 29 l . . sup . ( 2 ) 9 . 26 2 . tmcs ( trimethyl - 1 . 17 l . 9 . 26 2 . chlorosilane ) dma ( n , n - dimethyl - 0 . 696 l . 5 . 48 1 . 2aniline ) dma . hcl 1 . 49 kgw of solution . sup . ( 3 ) 2 . 82 0 . 61d -(-)- 2 - p - hydroxyphenyl - glycine chloride 1 . 26 kgw of 82 % pure 4 . 63 1 . 0hydrochloridewater 12 . 5 l . or 50 % of -- -- measured acylation mix volume -- also as neededsodium chloride 2 . 5 kgw or 20 % of the -- -- water volume6 n hcl as needed -- -- 15 % la - 1 resin / mibk 37 . 5 l . of la - 1 in mibk -- --( mila ) ( 5 . 625 l . la - 1 in 37 . 5 l . total volume ) filter - aid 500 g . of acid wash -- --( diatomaceous earth ) ( or low fe content ) notes : . sup . ( 1 ) molecular sieve drying removes water and methanol from the mecl . sub . 2 . . sup . ( 2 ) this procedure calls for 2 moles of tea and tmcs . with the variations in input apa and mecl . sub . 2 ( recovered vs . new ) this level has been shown to give more consistent results . this procedure is also effective at 1 . 6 moles tea and tmcs . . sup . ( 3 ) 30 % wt / wt dma . hcl solution , 1 . 25 g / cc . __________________________________________________________________________ iii . safety trimethylchlorosilane ( tmcs ) - flammable . highly reactive with moisture to give off hcl . d -(-)- 2 - p - hydroxyphenylglycine chloride hydrochloride - highly reactive with moisture to give off hcl . tea . dma are both two well - known toxic chemicals which should be handled with the usual great care . amoxicillin hydrochloride - toxicity and allergenic properties are unknown . handle this with the same care as all penicillins . rest of chemicals are well - known and should be handled with normal precautions . 1 . to 20 l . of mecl 2 at 25 ° c ., add 1 kgw of 6 - apa . add 1 . 29 l . of tea at 25 ° to 28 ° c ., agitate 30 min . - 6 - apa should nearly dissolve . 2 . at 20 ° to 25 ° c . add 1 . 17 l . of tmcs . allow the temperature to rise 25 ° to 27 ° c . add the tmcs over a 5 - 10 min . period . hold 60 min . at 25 ° c . 3 . cool to 0 ° to 5 ° c . add 0 . 696 l . of dma and 1 . 49 kgw of dma . hcl solution . begin acylation immediately . 4 . sprinkle in 1 . 26 kgw d -(-)- 2 - p - hydroxyphenylglycine chloride hydrochloride in three aliquots as follows : add 1 / 3 of the d -(-)- 2 - p - hydroxyphenylglycine chloride hydrochloride ( 430 g .) at 0 ° to 5 ° c . over a 5 min . period . allow the acylation mix to cool back to about 3 ° c . add a second aliquot of d -(-)- 2 - p - hydroxyphenylglycine chloride hydrochloride rapidly . allow the temperature to rise to about 5 ° c . hold 10 min . while cooling back to & lt ; 5 ° c . add the final amount of d -(-)- 2 - p - hydroxyphenylglycine chloride hydrochloride ( 430 g . ), keeping the temperature below 10 ° c . -- if possible , 5 ° c .. sup . ( 4 ) age the acylation mix at 0 to 5 ° c . ( 3 ° c . preferably ) for 2 hr . 5 . the acylation mix must be polished . in the laboratory this is best accomplished as follows : a . to the cold acylation mix add 500 g . of low iron content filter - aid ( in the laboratory acid - washed filter - aid was used -- this contains 36 ppm fe and a kf of 0 . 05 %). do not allow &# 34 ; wet &# 34 ; filter - aid ( higher kf than 0 . 05 %) to come in contact with the acylation mix . b . hold approximately 5 min . and polish filter rapidly into 12 . 5 l . of well - agitated ice cold h 2 o ( or 50 % of the measured acylation mix volume ). wash the filter cake with methylene chloride . 6 . the amoxicillin hydrochloride is crystallized at 0 -- 5 ° c . as follows :. sup . ( 5 ) a . sprinkle in about 1 / 8 of the total 2 . 5 kgw nacl ( about 300 g .) into the 0 ° to 5 ° c . hydrolysis mix . seed with 10 g . of amoxicillinn hydrochloride if possible -- if not , add a little more salt ( about 100 g .). hold for about 5 to 10 minutes ; should observe a heavy bed of amoxicillin hydrochloride crystals -- if not , add a little more salt . b . once a heavy bed of crystals is established ( this should not take more than 10 min . -- the hydrolysis mix is not too stable ), add another 1 / 8 portion of salt . total added is 25 %. hold 5 minutes . c . now add the remaining 75 % total salt ( about 1 . 25 kgw ) over 10 to 15 min . the entire operation should not take more than 30 min ., however it is important that a good amoxicillin hydrochloride slurry be established at a low salt concentration . this leads to low dma content in the final amoxicillin trihydrate . d . after all the salt is added , make sure the ph of the slurry is at 1 . 3 to 1 . 5 , adding 6 n hcl if necessary . agitate 30 min . at 0 °- 5 ° c . filter , wash with mecl 2 and 2 . 5 to 4 l . of ice cold , clear , saturated ( 35 g . salt / 100 ml .) sodium chloride solution . pull dry enough under vacuum so that the product wet cake can be safely handled . 7 . at 25 ° c . convert the amoxicillin hydrochloride to amoxicillin trihydrate by adding it to a mixture of 37 . 5 l . of 15 % la - 1 in mibk . sup . ( 6 ) and 3 . 75 l . of h 2 o . sprinkle the cake into the mila with good agitation . sprinkle at a slow rate , allowing the cake to disperse and convert to 3h 2 o . 8 . hold 2 to 3 hr . at 25 ° c ., collect by filtration , wash thoroughly with mibk and then with 2 l . of cold h 2 o . cake may be flashed with acetone . dry at 40 ° c . for 14 to 16 hr . the yield is usually 1 . 50 - 1 . 59 kgw of 98 % pure amoxicillin trihydrate ( bio ) from 98 . 7 % pure 6 - apa ; 77 - 82 % activity yield . the dma content is usually & lt ; 10 ppm . the following represents recent laboratory data on the isolation of amoxicillin hydrochloride from anhydrous acylation mix . the amoxicillin hydrochloride is then converted to amoxicillin trihydrate by slurrying in la - 1 resin ( dissolved in mecl 2 or mibk ) and 10 % water . the process represents a very efficient method of preparing good quality , low dma (& lt ; 15 ppm , usually & lt ; 10 ppm ) amoxicillin trihydrate . it has the advantage of excellent yields and high productivity over other known methods of preparing amoxicillin . 1 . a procedure for the preparation of amoxicillin trihydrate via anhydrous acylation and isolation via the amoxicillin hydrochloride intermediate is set forth above . 2 . lab experiments gave 77 to 82 % activity yields to amoxicillin trihydrate from 6 - apa . a normal isolation leaves 6 to 9 % activity assayed as amoxicillin in the salt mother liquor ; 2 to 3 % amoxicillin in the la - 1 mother liquor and approximately 3 % unreacted 6 - apa . 3 . the major problem has been maintaining a dma content of less than 15 ppm in the final amoxicillin trihydrate . this was accomplished most consistently by : a . mixing acylation mix with a half volume water , followed by slow addition of solid nacl ( 20 % of the water volume by weight ). b . slow addition of amoxicillin hydrochloride cake to the la - 1 dissolved in mibk or mecl 2 ( mila or mela ). 4 . when normal production grade 6 - apa is used for an acylation , a polish filtration of the anhydrous acylation mix must be used . 5 . it has not been possible in this laboratory to obtain standard amoxicillin yields without the addition of at least 0 . 5 mole of the hydrochloride of a weak base ( dma ) prior to acylation . quinoline can be substituted for dma if quinoline hydrochloride is used in the same ratio as dma hydrochloride . one acylation with isoquinoline was unsuccessful . 6 . the best acylation yields from 6 - apa to amoxicillin continue to be at a 1 mole d -(-)- 2 - p - hydroxyphenylglycine chloride hydrochloride level . in one comparison , 0 . 95 mole d -(-)- 2 - p - hydroxyphenylglycine chloride hydrochloride gave a 3 % better yield to amoxicillin based on the acid chloride than 1 mole . listed in table i are the results obtained when amoxicillin cake ( from amoxicillin + 6 n hcl ) is slurried in salt solution over a ph range of 0 . 5 to 1 . 75 . this shows that amoxicillin . hcl has very little solubility in 20 to 30 % nacl solution . it is also quite stable at ph 1 . 0 to 1 . 5 . when the hydrochloride is precipitated from acylation mix , 6 to 9 % amoxicillin is assayed in the salt solution . these losses are higher than expected from the solubility table and may be due partly to the formation of para - methoxy - ampicillin . hcl from d -(-)- 2 - p - hydroxyphenylglycine chloride hydrochloride containing para - methoxy - phenylglycyl chloride . hcl . previously , amoxicillin hydrochloride to amoxicillin trihydrate experiments from lab and plant acylation mixes only gave 65 to 70 % yields . this was due to quenching the mixes in 10 to 20 % by volume of saturated salt solutions at ph 0 . 5 . these low yields must have been caused by severe decomposition in the highly concentrated low ph solution . table ii shows that excellent yields can be obtained when the water volume is increased to 50 % of the acylation mix volume . comparison of 15 to 30 % salt over a ph range of 0 . 3 to 1 . 5 ( adjusted after the hcl cake precipitated ) showed that 25 to 30 % gave a product with unacceptable (& gt ; 15 ppm ) dma content . a level of 20 % at ph range 1 . 3 to 1 . 5 gave the best results in the lab . these experiments were done with recrystallized 6 - apa ; no polish filtration step required . plant grade 6 - apa usually contains insoluble dark color bodies which must be removed . table iii shows that polish filtration of hydrolysis mixes ( ph 1 . 5 ) through a dicalite - coated filter resulted in slightly lower yields . it has been demonstrated that amoxicillin hydrochloride will precipitate from a stirred hydrolysis mix when seeded or stirred too long . the safest method is to polish the anhydrous acylation mix . the use of filter - aid as admix in the lab ( only experience is 50 % by weight , filteraid to apa ) resulted in yields of 76 to 79 % amoxicillin trihydrate . product colors were higher than expected but generally within specifications . the use of acidwashed filter - aid did not result in improved yields or color . table iv lists experiments in which the amoxicillin hydrochloride was precipitated by various techniques with nacl used as a solid and solution . it was theorized that the use of a salt solution as a precipitant might result in crystallization of the hcl &# 39 ; d salt at low nacl concentrations . this should have led to amoxicillin trihydrate products of consistently low dma content but it did not prove to be true in the experiments tried . the most successful results came when 20 % salt was sprinkled into the hydrolysis mix over 30 min . table v gives some idea of the stability of the amoxicillin hydrochloride slurry over a 16 hr . period . at 0 ° to 5 ° c . the maximum yield loss was only 3 %. crystallization of the amoxicillin hydrochloride slurry at 25 ° c . resulted in a lower weight precipitated and the remaining product was found in the mother liquor . however , no attempt was made to precipitate the product cold and then warm to 25 ° c . the advantage might be to precipitate a product with half the dma content of the cold slurried product . table vi lists some experiments on the amoxicillin hydrochloride to amoxicillin trihydrate conversion slurries . the data indicate that 15 % la - 1 in mibk or mecl 2 ( containing 10 % h 2 o ) works well . acetone washing did not seem to influence the dma content . use of other solvents such as butanol or heptane did not reduce dma contents ( product is quite soluble in wet butanol system ). in table vii the use of the hydrochloride of a weak base ( dma , quinoline or isoquinoline ) was investigated . omitting the weak base . hcl resulted in lower yields when compared to the standard procedure . it is also interesting to note that the amount of tea . tmcs influences the offset in yield . in most of the experiments ( not all ) the residual apa content was higher when the weak base . hcl was omitted . it is also interesting to note that the base content of amoxicillin trihydrate from quinoline acylation is much higher than for dma acylations . no attempt was made to do direct crystallizations - all products were prepared via the hcl intermediate . table viii represents the brief experiences at 0 . 9 , 0 . 95 and 1 . 0 mole d -(-)- 2 - p - hydroxyphenylglycine chloride hydrochloride . as indicated , 1 mole d -(-)- 2 - p - hydroxyphenylglycine chloride hydrochloride gave the best apa yields but 0 . 95 mole gave a better d -(-)- 2 - p - hydroxyphenylglycine chloride hydrochloride yield . in all acylations there is approximately a 5 to 10 % hole in the material balance . thus , addition of 10 % extra d -(-)- 2 - p - hydroxyphenylglycine chloride hydrochloride does not result in a corresponding increase in amoxicillin trihydrate yield . table i______________________________________solubility dataamoxicillin hydrochloride vs ph & amp ; % naclbio potency , mcg ./ ml . ph h . sub . 2 o 5 % nacl 10 % nacl 20 % nacl 30 % nacl______________________________________0 . 5 10600 5600 5700 2130 12601 . 0 32000 8500 4560 1980 15001 . 25 53500 9100 4680 1770 11301 . 5 53500 10000 5650 2070 11301 . 75 55000 12300 6000 2100 1180______________________________________ table ii__________________________________________________________________________ph . salt concentration vs . yield and dma content of amoxicillin__________________________________________________________________________trihydrate % bio % dma % experiment ph scm * mcg ./ mg . act . yld . klett ppm ash cl - __________________________________________________________________________add aliquots of acylation mix a 1 . 3 82 . 3 857 81 48 31 0 . 2 0 . 34to 50 % h . sub . 2 o - hold 10 min . - b 1 . 0 81 844 79 49 46 0 . 1 . 16add 30 % salt - seed - c 0 . 3 81 . 2 862 80 . 4 43 32 0 . 1 0 . 14convert 15 % mela d as is 81 . 2 849 79 . 2 50 41 0 . 1 0 . 26 ( 1 . 4 - 1 . 5 ) add aliquots of acylation mix as isto 50 % h . sub . 2 o ( 1 . 4 - 1 . 5 ) a hold 10 min , add 15 % nacl - as is 79 . 0 866 78 . 6 44 9 & lt ; 0 . 1 0 . 15 1 shot ( 1 . 4 - 1 . 5 ) b hold 10 min , add 20 % nacl - as is 83 . 0 868 82 . 6 45 7 & lt ; 0 . 1 0 . 09 1 shot ( 1 . 4 - 1 . 5 ) c hold 10 min , add 25 % nacl - as is 84 . 0 866 83 . 5 65 18 & lt ; 0 . 1 0 . 22 1 shot ( 1 . 4 - 1 . 5 ) __________________________________________________________________________ *% scm refers to stoichiometric yield , that is , percent yield assuming pure reagents and pure product . table iii__________________________________________________________________________polish filtering acylation mix or hydrolysis mix prior to amoxicillinhydrochloride ppt . step__________________________________________________________________________ analyses on amoxicillin trihydrate__________________________________________________________________________ produced % h . sub . 2 o % act . yd . hyd . % % bio of amoxicillinstep nacl polish step experiment scm mcg / mg trihydrate dma ash klett__________________________________________________________________________60 20 - hyd . mix add h . sub . 2 o polish - process 77 . 5 866 77 . 4 8 & lt ; . 1 55 slow &# 34 ; &# 34 ; &# 34 ; sep . phases - cryst . h . sub . 2 o -- 76 . 9 866 76 . 9 7 & lt ; . 1 39 mecl . sub . 250 &# 34 ; &# 34 ; add h . sub . 2 o - polish - process 75 . 5 874 75 . 8 27 . 6 . sup . ( 1 ) 0 . 1 57 &# 34 ; &# 34 ; acyl . mix use dry f . a .. sup . ( 2 ) as admix 79 870 79 . 3 11 0 . 1 82 &# 34 ; &# 34 ; &# 34 ; 5 - μ funnel - n . sub . 2 bag - no f . a . 77 . 6 875 78 12 . 8 & lt ; 0 . 1 74 &# 34 ; 24 - &# 34 ; add mix - regular f . a .. sup . ( 2 ) 76 836 73 . 9 15 & lt ; 0 . 1 93 slow &# 34 ; &# 34 ; &# 34 ; add mix - wet f . a .. sup . ( 2 ) 76 . 8 858 76 . 7 18 & lt ; 0 . 1 94 &# 34 ; &# 34 ; &# 34 ; add mix - dry f . a .. sup . ( 2 ) 77 . 4 883 78 . 4 -- -- -- 60 20 &# 34 ; dry f . a . - use as precoated 79 . 7 836 77 . 5 10 & lt ; 0 . 1 80 filter &# 34 ; &# 34 ; hyd . mix polish as above 76 . 4 849 73 . 5 & lt ; 0 . 5 & lt ; 0 . 1 5950 &# 34 ; acyl . mix use acid - washed f . a .. sup . ( 2 ) as 77 . 7 840 75 . 9 10 & lt ; 0 . 1 119 admix__________________________________________________________________________ notes :- . sup . ( 1 ) only one sample sent in for dma assay - on some samples variability can be as high as 100 %. . sup . ( 2 ) &# 34 ; dry f . a .&# 34 ; = acetone - washed and dried filter - aid . &# 34 ; regular f . a .&# 34 ; = filter - aid as it comes from production . &# 34 ; wet f . a . &# 34 ; = filter - aid that has been slurried in water and air - dried . &# 34 ; acid - washed f . a .&# 34 ; = washed in hcl - neutralized - acetone - washed and dried . table iv__________________________________________________________________________amoxicillin trihydrate dma content etc . vs . technique of amoxicillinhydrochloride precipitation__________________________________________________________________________ %% totalvol . added % bio % dmah . sub . 2 o salt ph experiment scm mcg / mg act . yd . ppm comments__________________________________________________________________________50 20 1 . 4 - control - add salt - 1 shot 83 868 82 . 6 7 recryst . apa - no 1 . 5 polish filtration step &# 34 ; &# 34 ; &# 34 ; add acyl . mix to salt - h . sub . 2 o 75 . 8 849 73 . 5 8 &# 34 ;&# 34 ; &# 34 ; &# 34 ; add salt - 1 shot 80 . 5 874 80 . 4 18 &# 34 ;&# 34 ; &# 34 ; &# 34 ; add salt - 2 shots over 10 min . 79 . 5 887 79 . 5 7 &# 34 ; 75 &# 34 ; &# 34 ; add salt - 1 shot 79 . 4 870 79 . 4 7 &# 34 ; 100 &# 34 ; &# 34 ; add salt - 1 shot 78 . 4 891 78 . 4 7 &# 34 ;&# 34 ; &# 34 ; &# 34 ; dilute acyl . mix w / 100 % mecl . sub . 2 78 870 78 6 &# 34 ; 30 &# 34 ; &# 34 ; sop - slow addition 80 . 5 858 79 . 3 13 &# 34 ; 15 &# 34 ; &# 34 ; sop - slow addition 77 . 6 849 75 . 6 9 &# 34 ; 20 &# 34 ; 1 . 3 add salt solution to hyd . mix 78 . 4 879 78 . 4 10 &# 34 ; slowly30 &# 34 ; &# 34 ; add salt solution to hyd . mix 76 870 76 8 &# 34 ; slowly20 &# 34 ; &# 34 ; add salt solution to hyd . mix 78 . 8 870 78 . 8 15 &# 34 ; rapidly50 &# 34 ; &# 34 ; add solid salt slowly 77 . 7 840 75 . 9 10 polish filtration step - plant apa20 &# 34 ; &# 34 ; use 30 % vol . salt solution + 76 . 9 849 76 . 5 18 &# 34 ; solid40 &# 34 ; &# 34 ; use 10 % vol . salt solution + 79 840 77 . 2 13 &# 34 ; solid__________________________________________________________________________ table v__________________________________________________________________________stability of amoxicillin hydrochloride slurry at ph 1 . 4 → 1 . 7 ( unadjusted ) - 25 % nacl solution__________________________________________________________________________ temp . amoxicillin . hclsample held time 100 ml . % of control mcg . in ml__________________________________________________________________________1 0 . 5 ° c . 0 . 5 hr . 7 . 63 100 370 , 0002 &# 34 ; 1 hr . 7 . 95 104 360 , 0003 &# 34 ; 1 . 5 hr . 7 . 64 100 370 , 0004 &# 34 ; 2 hr . 7 . 85 103 320 , 0005 &# 34 ; 3 hr . 7 . 50 98 360 , 0006 &# 34 ; 16 hr . 7 . 37 96 . 6 360 , 0007 25 ° c . 2 hr . 6 . 4 84 610 , 000__________________________________________________________________________dma content of amoxicillin hydrochloride samples prepared at 0 to5 ° c . was 6390 ppm . dma content of sample number 7 was 3300 ppm . the dried amoxicillin hydrochloride cake in sample number 2 was convertedto amoxicillin trihydrate , 82 % yield , bio 862 , dma 33 . table vi__________________________________________________________________________conversion step__________________________________________________________________________ analyses on amoxicillin trihydrate produced__________________________________________________________________________ % % bio % dmah . sub . 2 o nacl conversion mix experiment scm mcg / mg act . yd . ppm__________________________________________________________________________50 20 ph 5 , 15 % mela as in the example above 79 . 5 849 77 . 5 6 &# 34 ; &# 34 ; ph 5 , 20 % mela as in the example above 78 . 8 858 77 . 6 8 &# 34 ; &# 34 ; ph 5 , 15 % mila as in the example above 79 . 4 862 78 . 6 4 &# 34 ; &# 34 ; ph 5 , 15 % mela slurry in acetone 78 . 7 853 77 . 1 9 &# 34 ; &# 34 ; 15 % mela , ph unadjusted heavy mecl . sub . 2 was on amoxi - 78 . 5 853 76 . 9 17 cillin hydrochloride cake prior to conversion &# 34 ; &# 34 ; 15 % mela , ph unadjusted add conversion mix to the hcl cake 81 . 3 78 . 9 10 &# 34 ; &# 34 ; 15 % mela , ph unadjusted acetone wash amoxicillin tri - 81 . 3 831 77 . 6 12 hydrate in filter funnel &# 34 ; &# 34 ; 15 % mela , ph unadjusted control 79 . 9 888 79 . 9 4 &# 34 ; &# 34 ; 15 % mila , ph unadjusted as in the example above 77 . 9 879 77 . 9 5 &# 34 ; &# 34 ; 20 % bula , ph unadjusted as in the example above 58 . 7 875 58 . 7 18 &# 34 ; &# 34 ; 15 % la - 1 in heptane , as in the example above 78 . 4 853 76 . 8 12 ph unadjusted__________________________________________________________________________ table vii__________________________________________________________________________use of dma - quinoline - isoquinolineimportance of the base . hcl addition & amp ; relation to ester__________________________________________________________________________make - up analyses on amoxicillin trihydrate produced__________________________________________________________________________ % % % bio % baseester base base . hcl h . sub . 2 o salt scm mcg / mg act . yd ppm comments__________________________________________________________________________2 . 0 moles tmcs - tea 1 . 2 dma 0 . 6 dma . hcl 50 24 82 . 5 874 82 . 5 6 recryst . 6 - apa input &# 34 ; &# 34 ; &# 34 ; &# 34 ; 0 . 61 &# 34 ; &# 34 ; 20 83 868 82 . 6 7 &# 34 ; 1 . 6 &# 34 ; &# 34 ; &# 34 ; 0 &# 34 ; &# 34 ; &# 34 ; 74 874 74 6 &# 34 ; 2 . 0 &# 34 ; &# 34 ; quin 0 quin . hcl &# 34 ; 24 68 . 1 849 66 . 4 82 &# 34 ; 1 . 6 &# 34 ; &# 34 ; &# 34 ; 0 &# 34 ; &# 34 ; &# 34 ; 77 858 75 . 9 75 &# 34 ;&# 34 ; &# 34 ; 1 . 0 &# 34 ; 0 &# 34 ; &# 34 ; 20 73 . 2 883 73 . 2 33 &# 34 ; 2 . 0 &# 34 ; &# 34 ; &# 34 ; 0 . 125 &# 34 ; &# 34 ; 24 73 . 4 870 73 . 4 24 &# 34 ;&# 34 ; &# 34 ; &# 34 ; &# 34 ; 0 . 25 &# 34 ; &# 34 ; &# 34 ; 75 . 0 866 75 24 &# 34 ;&# 34 ; &# 34 ; &# 34 ; &# 34 ; 0 . 5 &# 34 ; &# 34 ; &# 34 ; 80 . 4 871 80 . 4 17 &# 34 ;&# 34 ; &# 34 ; &# 34 ; &# 34 ; 0 . 6 &# 34 ; &# 34 ; &# 34 ; 80 . 6 866 80 . 1 13 &# 34 ;&# 34 ; &# 34 ; &# 34 ; &# 34 ; 0 . 75 &# 34 ; &# 34 ; &# 34 ; 78 . 5 862 77 . 7 24 &# 34 ;&# 34 ; &# 34 ; 1 . 2 iso - 0 . 6 isoquin . &# 34 ; &# 34 ; 55 848 53 . 5 na &# 34 ; quin hcl__________________________________________________________________________ table viii__________________________________________________________________________d -(-)- 2 - p - hydroxyphenylglycine chloride hydrochloride - amoxicillintrihydrate yield viaamoxicillin hydrochloride process__________________________________________________________________________ % % mole d -(-)- 2 - p - hydroxyphenyl - apa bio % d -(-)- 2 - p - hydroxyphenylglycineglycine chloride hydrochloride scm mcg / mg act . yd . chloride hydrochloride act . __________________________________________________________________________ yd . 1 . 0 77 . 7 840 78 . 2 78 . 20 . 9 70 . 9 845 69 . 7 77 . 40 . 95 76 . 3 875 76 . 3 81 . 4__________________________________________________________________________