Chemical Stability
`of Pharmaceuticals
`
`A Handbook for Pharmacists
`
`Second Edition
`
`Kenneth A. Connors
`
`School of Pharmacy, The University of Wisconsin
`
`Gordon L. Amidon
`
`_
`
`College of Pharmacy, The University of Michigan
`
`Valentino J. Stella
`
`School of Pharmacy, The University of Kansas
`
`A Wiley-Interscience Publication
`
`JOHN WILEY & SONS
`
`New York 0 Chichester
`
`0 Brisbane 0 Toronto 0 Singapore
`
`MYLAN ET AL. - EXHIBIT 101
`
`000
`
`MYLAN ET AL. - EXHIBIT 1018
`
`0001
`
`

`
`
`
`-~.___.‘,._-~.
`
`'
`
`“-"---x._
`
`Copyright © 1986 by John Wiley & Sons, lnc.
`
`All rights reserved. Published simultaneously in Canada.
`
`Reproduction or translation of any part of this work
`beyond that permitted by Section 107 or 108 of the
`1976 United States Copyright Act without the permission
`of the copyright owner is unlawful. Requests for
`permission or further information should be addressed to
`the Permissions Department. John Wiley & Sons, Inc.
`
`Library of Congress Cataloging in Publication Data:
`Connors, Kenneth A. (Kenneth Antonio), I932-
`Chemical stability of pharmaceuticals.
`
`“A Wiley-lnterscience publication.“
`Includes bibliographies and index.
`ll. Stella,
`1. Drug stability.
`1. Amidon, Gordon L.
`Valentino 1-. I946--
`111. Title.
`[DNLM:
`1. Drug
`Stability—handbooks.
`2. Kinetics——handbooks.
`QV 735 C752c]
`
`RSfl+C% I%6 myqs
`ISBN o—471-s79s5.x
`
`wamfi
`
`Printed in the United States of America
`
`l09876543'.7.l
`
`0002
`
`0002
`
`

`
`Contents
`
`PART ONE:
`
`PRINCIPLES
`
`Chapter 1.
`
`Introduction
`
`A. Stability Prediction by the Pharmacist,
`B. Other Sources of Information,
`5
`
`3
`
`Chapter 2. Stability Calculations
`
`A. Rate Equations,
`
`8
`
`The Order of Chemical Reactions,
`1.
`2. First-Order Calculations,
`11
`3.
`Zero—Order Calculations, 15
`
`8
`
`3
`
`8
`
`B. Temperature Effects,
`
`18
`
`1. Activation Energy Calculations, 18
`2.
`Q1 —Value Calculations:
`Approximate
`Meéhod, 22
`
`C.
`
`Shelf—Life Estimation Methods, 26
`
`Chapter 3.
`
`Interpretation of Kinetic Data
`
`32
`
`The Transition—State Theory, 32
`A.
`B. Medium Effects, 38
`C, Catalysis, 41
`
`D.
`
`pH Effects, 43
`
`1.
`2.
`
`V—Graphs, 44
`Sigmoid Curves, 47
`
`3. Bell-Shaped Curves, 52
`
`E.
`
`Some Practical Matters, 55
`
`1. Using pH—Rate Profiles, 55
`
`2. Using Activation Energies, 59
`
`chapter 4. Hydrolysis and other Acyl Transfers
`
`63
`
`A. Nature of
`
`the Reaction, 65
`
`B. Catalysis, 69
`
`C. Structure and Reactivity, 73
`
`ix
`
`000
`
`0003
`
`

`
`C. Structure and Reactivity, 73
`
`D. Stabilization of Pharmaceuticals, 76
`
`E.
`
`Pharmaceutical Examples, 77
`
`Chapter 5. Oxidation and Photolysis
`
`82
`
`A. Oxidation, 83
`1. Nature of Oxidation, 83
`2. Kinetics of Oxidation, 85
`
`3. Oxidative Pathways of
`Interest, 93
`Inhibition of Oxidation, 97
`
`4.
`
`Pharmaceutical
`
`B. Photolysis, 105
`
`1. Energetics of Photolysis, 105
`2. Kinetics of Photolysis, 107
`3. Photolytic Reactions of Pharmaceutical
`Interest, 108
`Prevention of Photolytic Reactions, 111
`
`4.
`
`Chapter 6.
`
`So1id—State Chemical Decomposition
`
`115
`
`A. Kinetics of So1id—State Decomposition, 116
`B. Pharmaceutical Examples of So1id—State
`
`Decomposition, 119
`1.
`Pure Drugs, 119
`2. Drug—Excipient and Drug~Drug
`Interactions in Solid Dosage Forms, 126
`
`C. Methods of Stabilization, 132
`
`Chapter 7. Strategy and Tactics of Stability
`Testing
`
`135
`
`Regulatory Requirements, 136
`A.
`B. Stability Protocols, 145
`1. General Considerations, 145
`
`2. Experimental Designs, 148
`
`C.
`
`Interpretation of Data, 154
`
`000
`
`0004
`
`

`
`Methyl Paraben
`
`GENERAL
`
`Names
`
`Methyl paraben; methyl p~hydroxybenzoate.
`
`Structure
`
`H0
`
`fl
`c—ocH3
`
`C H 0
`8
`8
`
`3
`
`mol. wt. 152.15
`
`Forms Available
`
`Methyl paraben.
`
`Physical Properties
`
`11g dis-
`Solubility:
`Melting point 126 to 128°C.
`10 mL of
`solves in 400 mL of water,
`3 mL of alcohol,
`Soluble in
`ether;
`1
`g
`in 50 mL of water at 80°C.
`
`acetone and glycerin (1).
`
`Stability Summary
`
`Methyl paraben undergoes acid—catalyzed and base-
`catalyzed ester hydrolysis,
`the pH of maximum stabil-
`ity being near
`pH 4.
`The base—catalyzed kinetics are
`complicated by ionization of
`the phenolic group,
`so
`that hydrolysis at very high pH occurs more slowly
`than would be anticipated for
`a
`simple uncharged
`ester. Hydrolysis is followed by decarboxylation of
`p—hydroxybenzoic acid to give phenol.
`
`580
`
`0005
`
`0005
`
`

`
`Drug Kinetics
`
`581
`
`DRUG KINETICS
`
`Reactions and Rate Equation
`
`Methyl
`group.
`
`paraben undergoes hydrolysis of
`
`the ester
`
`yielding p—hydroxybenzoic acid and methanol.
`
`H0
`
`CDOCI-I3 + H20 ——-> H0
`
`CDDH + CHaOH
`
`( 1 )
`
`The
`
`reaction is first order with respect
`
`to the ester
`
`Since the phenolic group is ionizable,
`concentration.
`and both the neutral and anion forms can undergo reac-
`tion,
`these are the expected important reactions:
`
`H-F
`MH + H20 ————€> products
`
`OH“
`MH + H20 ——-—-€>
`
`products
`
`_
`
`H
`
`OH"
`+ H20 ~—~m~e> products
`
`(2)
`
`(3)
`
`(4)
`
`where MH represents neutral methyl paraben.
`responding rate equation is
`
`The cor-
`
`rate = kH[MH][H+]
`
`+ k'[MH][0H‘]
`
`+ k"[M‘][0H']
`
`(5)
`
`the p-
`(2) have reported that
`Sunderland and Watts
`hydroxybenzoic acid produced in the ester hydrolysis
`can undergo decarboxylation to yield phenol.
`In the
`
`presence of oxygen, at high temperature, several oxi-
`dation reactions of
`the phenol may subsequently occur.
`
`pH~Rate Profile
`
`is the pH—rate profile for the hydrolysis of
`Figure 1
`methyl paraben at 130.5°C (2).
`The data are consis-
`tent with rate equation (5).
`The pKa at 130.5°C is
`7.65;
`the inflection point
`in the pH 7-9 range is a
`consequence of
`the ionization of
`the substrate.
`In
`
`the slope is -1.0, and the reac-
`to 3
`the pH region 1
`tion is dominated by the RH term;
`from pH 5
`to 7
`the
`k‘
`term is most
`important, and from pH 9
`to 11 the k"
`term controls the rate.
`
`000
`
`0006
`
`

`
`582
`
`Methyl Paraben
`
`-logk(s“)
`
`0
`
`2
`
`4
`
`6
`
`8
`
`1'0
`
`12
`
`pH—rate profile for
`FIGURE 1. Methyl paraben.
`hydrolysis of methyl paraben at 130.5°C (2).
`
`the
`
`temperatures
`lower
`Fragmentary pH—rate profiles at
`(3-5);
`the shapes
`have been reported by other workers
`of
`these curves are consistent with the result
`in
`Figure 1.
`
`the pH—rate profile Sunderland
`From the analysis of
`and Watts found the rate constants
`
`RH = 0.151 M"1 s-1
`
`k’
`
`= 5.90 M-1 s-1
`
`k"
`
`= 0.32 M-1 s-1
`
`the decarboxylation of p-
`The pH—rate profile for
`a maximum near
`pH 7;
`the
`hydroxybenzoic acid shows
`curve can be fitted with the rate equation
`
`rate = k1[H2A]
`
`+ k2[HA‘]
`
`+ k3[A2”]
`
`where H2A represents p—hydroxybenzoic acid.
`
`At
`
`0007
`
`0007
`
`

`
`Drug Kinetics
`
`583
`
`130.5°C,
`4 67 aiui
`are (2)
`
`the acid dissociation constants are pK1 =
`pK2
`= 8.84,
`and the derived rate constants
`
`k1 = 1.94 x 10"6 s"1
`
`kg = 5.31 x 10-6 s-1
`II
`
`3.00 x 10-7 s-1
`
`7:’ (.0
`
`Activation Energy
`
`Several authors have studied the activation parameters
`
`Table 1 lists the observed enthalpies and en-
`(2-5).
`tropies of activation found by Sunderland and Watts
`
`(2).
`
`TABLE 1. Apparent Activation Parameters for
`Hydrolysis of Methyl Paraben (2)
`
`
`the
`
`pH
`AH*
`(kJ-mo1‘1)
`AS* (JK’1-mol“1)
`
`
`1.26
`6.58
`
`8.10
`
`0.01 M NaOH
`
`90.3
`95.2
`
`88.2
`
`52.8
`
`-92
`-94
`
`H91
`
`-165
`
`0.10 M NaOH
`56.7
`-134
`
`
`The activation parameters assigned to the individ~
`ual rate constants must
`take into account
`the heats of
`ionization of
`the reactant and the water.
`These
`
`values were calculated (2):
`
`
`AH* (kcal-mol‘1)
`Rate Constant
`
`
`21.8
`kH
`11.0
`k‘
`12.6
`R"
`
`
`00
`
`0008
`
`

`
`584
`
`Methyl Paraben
`
`The activation enthalpy of kg for the decarboxyla—
`tion is 26.2 kcal/mol.
`
`The maximum stability of methyl paraben is at about
`pH 4; extrapolation of
`the data obtained at higher
`temperatures leads to an estimate (3) of 241 1 47
`years as
`the half—life at 25°C and pH 4.
`Blaug and
`Grant
`(5) estimate that
`the half—life is 72 days at pH
`9.16 and 25°C in 0.1 M phosphate buffer
`(the rate is
`accelerated by phosphate).
`The predicted extent of hydrolysis (3) of methyl
`paraben under autoclaving (121.5°C for 20 min) was
`0.09% at
`pH 3 and 0.05% at
`pH 4.
`Raval and Parrott
`(4)
`subjected methyl paraben to autoclaving at 121°C
`for 30 min,
`finding 5.5% decomposition at
`pH 6 and
`42.0% decomposition at
`pH 9.
`These losses were close
`to the values Dredicted by calculation with the acti-
`vation energy.
`Sunderland and Watts
`(2) emphasize
`that methyl paraben is unstable under
`typical auto-
`clave conditions unless the pH is 3
`to 6.
`
`Other Data
`
`The rate of methyl paraben hydrolysis increases
`with an increase in ionic strength, but
`the effect
`is
`small (5).
`The rate of hydrolysis is sensitive to phosphate
`concentration. as shown by the data in Table 2 (5).
`
`TABLE 2. Effect of Phosphate Concentration on
`Hydrolysis of Methyl Parabena
`
`
`106k (s‘1)
`Total Phosphate Concentration (M)
`_____________________HH_______________________"________
`
`/
`
`'
`
`0.02
`0.04
`0.08
`
`0.10
`0.20
`
`3.18
`3.57
`4.56
`
`5.29
`7.46
`
`aAt 70°C,
`
`pH 8.24,
`
`ionic strength 0.6 M.
`
`0009
`
`0009
`
`

`
`References
`
`585
`
`FORMULATIONS AND COMBINATIONS
`
`Degradation Reactions
`
`likely degradation reac-
`Ester hydrolysis is the most
`tion in aqueous formulations.
`In formulations con-
`
`taining hydroxylic solvents such as alcohol or propyl-
`ene glycol,
`transesterification (solvolysis) is a pos-
`sibility.
`It has been reported that
`a preparation of
`ltheophylline olamine stabilized with parabens exhib~
`ited extensive loss of parabens through reaction of
`
`the parabens with ethanolamine to form N—(2—hydroxy—
`ethyl)-4—hydroxybenzamide, H0—C6H4-CONHCHZCHZOH (6).
`Methyl paraben has been found to bind noncovalently
`to the macromolecule cetomacrogol
`(7), as does propyl
`paraben.
`Presumably the bound form is ineffective as
`
`a preservative. Often the parabens are used in pairs,
`since their action in combination is considered to be
`
`The binding of methyl paraben and propyl
`synergistic.
`paraben to cetomacrogol
`is competitive,
`and a
`larger
`fraction of
`total parabens exists in the unbound state
`in a mixture of
`the two compared with either singly.
`
`Stabilization Methods
`
`Stabilization is best achieved by regulating the pH in
`
`accordance with Figure 1.
`Hydrolysis is a potential
`problem at autoclave temperatures and pH values above
`6.
`
`REFERENCES
`
`1. Remington's Pharmaceutical Sciences (15th ed.),
`Philadelphia College of Pharmacy and Science,
`Philadelphia, 1975.
`
`2.
`
`V. B. Sunderland and D. W.
`
`Watts, Int.
`
`J. Pharma-
`
`ceut., 19,
`
`1
`
`(1984).
`
`3.
`
`A. Kamada, N. Yata, K. Kubo; and M. Arakawa, Chem.
`Pharm. Bull., 21, 2073 (1973).
`
`4.
`
`N
`
`.
`
`N. Raval and E. L.
`
`Parrott. J. Pharm. Sci., 56,
`
`274 (1967).
`
`001
`
`0010
`
`

`
`586
`
`Methyl Paraben
`
`5.
`
`S. M. Blaug and D. E. Grant, J. Soc. Cosmet.
`
`Chem., 25, 495 (1974).
`
`6.
`
`and M. A. Kreienbaum,
`Juenge, D. F. Gurka,
`E. C.
`J. Pharm. Sci., 70, 589 (1981).
`
`7.
`
`M. J. Crooks and K. F. Brown, J. Pharm. Pharma-
`
`co1., 26, 235 (1974).
`
`- Kenneth A. Connors
`
`(Wisconsin)
`
`0011
`
`0011
`
`

`
`Prccalne
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`

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`
`DEHE KINETICS
`
`neactinna and Rana Equatian
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`Ifish important rtnctlon cnntrjbutinz to the 135k“.
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`

`
`Drug H.'i.I'|.EI'.l|'.j:B:
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`BB5
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`n3n—ph—cnnne+-—J5L—a products
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`
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`
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`
`rate - EHEHEN-Eh-EflflRH‘]{H*]
`
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`
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`
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`1.D1 x 1o'5 fl'1 5'1.
`hug = 2.1? H'1 5'1.
`and kn“ =
`1.p5 x 1a‘? m'1 5'1.
`
`EH-Rate Profile
`
`tor the hydrolysis
`pH plat
`In thn lug h vs.
`Figure I
`of pcocalne at e1':.
`It can be quantitatively ac-
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`procaine below pH 2-5.
`the specific beau oatalyele of
`prfltpnuted prooaino frfll PH 5-5 1% 3-5 {HPDPDI-1.
`tho
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`pH 3.5 to 11.5 [nppro1.]. and the apepific bane ontol-
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`The Ilxlnun
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`H1 DH 3-5 End 3T'C.
`Lh: rate cnnntnnt 13 2.9fl
`1 1o‘5 3'1. corresponding to
`1 hnlf-life of about 63.5 h-
`
`0014
`
`0014
`
`

`
`E95
`
`Preeaine
`
`—aeeL:,,.,,::-'I
`
`D
`
`1
`
`2
`
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`5
`
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`
`I
`pH
`
`B
`
`9
`
`1n I1
`
`|: 1: 1:
`
`pH—:ate prnrile Eur hydrolysis
`Preneine.
`FIGURE 1.
`of procaine at 3T‘C [rate cnnstante in e'I]:
`f}.
`from
`Rtftrlrncir -1'.
`1'11.
`l'|‘I:I-II Reference 5; and U. Erel Refer-
`ence W. Enleulated from data at an“: ustng Arrhenius
`equation uith Ea - 13.3 keelimnl.
`
`flctifietiun Energy
`
`¢?} have
`and Hlzuchi et a].
`and Barnn [Bi
`Harfiui
`reperted these Arrhenius eetlvatlun energies IE3:
`fer
`the hydrolysis er procaine [eee Table 1:. where the
`rate eunetante are defined in Eqs.
`[ii
`threugh [5].
`THE Arrhenlua plat
`for hydrelyeie at
`pH 2-fl. Gerra-
`
`0015
`
`0015
`
`

`
`Formulations and Combinations
`
`E9?
`
`spending I’.-D resctiau I:I'5|'
`Figure 2.
`
`the Ru,“
`
`['flI1,:|t|3.
`
`is.
`
`ahuwn in
`
`TABLE 1. Activation Bnerziflfi
`Rsaetiens
`
`
`fur Frflflfliné Hydrfllrsis
`
`Reference
`Ea tkcslfnelh
`Rate cenetent
`_.?.,
`
`kg
`
`has
`
`ta.
`
`1e-e
`
`1E-”“
`
`1aa
`
`s
`
`7
`
`9
`
`Eerreeted Eur heat at
`- 3s_fl kcfilfifll.
`Apparent Eu
`innlzatlun of water {12.fl xealflel]. because u!
`lsek
`ar :ujtuh|e buffer to maintain Jew flH' eeneentratiene
`independent uf selutiun temperaturt-
`
`FIJRHULATTCIHS AND 'I3I'JHIII|H'.|1TI|JN5
`
`Dezredetien Heactlens
`
`Efluharcial phnrlanuulltfll preparatiuni HI hrntfilne are
`liuttefi
`to injgutghle dessee forms.
`at
`a result at
`thie the prinuipul degradations eeeur in thust
`indent-
`ahle dessge farm: utilizing natcr HE part at
`the Enl-
`uant ayaten_
`E13ugh1 and Buese [Bi have neted that
`in
`solutions buffered with acid-tree buffers {H-3-. phos-
`phate. burstup the advantage of high-ttuperature ster-
`lllsstinn Ls much
`less.
`This it hetfluie. although
`these hufrere usintsin fairly eflflfitflht
`PH HBIUEB flfler
`ulda temperature raugaa. hydraxyl Len esneeetratian
`chfingca very rapidly with temperature.
`The authors
`tnncluae that
`in unhurrered eelutiens er selutieue
`buffered with un1ne—type buffers.
`the hydrexvl
`inn
`euneentrstien is reughly independent
`flf
`temperature.
`and thus theee eyatene are better fflr HEE NEED flute-
`clnvinz is desirable.
`the
`ehewn that
`Higuchi and Huaag gs] have further
`eterili1atiun at ppucslue eelutiene is mere advanta-
`geeuely csrrlea put at higher
`than at
`lower
`teIpers-
`turee.
`This
`I: due to the relatively lei E3 of pre-
`
`0016
`
`0016
`
`

`
`698
`
`Procaine
`
`caine as compared with the high heat of activation
`needed for killing most
`thermally resistant organisms.
`The result of
`this is that at
`lower
`temperatures
`{e.g.,
`100°C}
`the drug will be degraded more
`rapidly
`than the organisms are killed, due to the differences
`in the heats of activation, whereas at autoclave
`temperatures {120°C)
`the reverse will be true.
`The influence of primary and secondary salt effects
`on the decomposition of procaine solutions via hydrol-
`ysis has been studied by Schmid {9}.
`At
`increased
`ionic strength (resulting from the addition of Nacl)
`the rate of unbuffered procaine hydrolysis was
`found
`to increase in accord with transltion—state theory of
`primary salt effects.
`When different buffer
`systems
`are used. however.
`the rate can be decreased due to
`changes in pH resulting from secondary salt effects.
`
`3.8
`
`4.0
`
`4.2‘
`
`4.4
`
`4.6
`
`4.8
`
`5.0
`
`5.2
`
`
`
`—logI-<ob,{s“J
`
`5.4
`2.90
`
`l_L|_JJ_1l_:
`2.95
`3.00
`3.05
`3.10
`10°xT
`
`3.15
`
`3.20
`
`Procaine. Arrhenius plot
`FIGURE 2.
`hydrolysis of procaine at pH 8.0.
`
`for alkaline
`
`0017
`
`0017
`
`

`
`Eorlulstlons and Eolhinations
`
`EH9
`
`in
`and Hooduaro {lol have observed that
`Thonas
`unhuffared 0.11 solutions or orooolno undergoing heat
`atariliiatluh the pa falls by almost ono unit over
`a
`s—n period, as
`shown in Tools 2. corresponding to an
`almost 1o-told ajouing of
`the reaction.
`This pH re-
`mained eonetaot
`for 3
`to I
`h and then conncnced to
`rise egojn_
`no reason for the latter observation has
`given.
`The author: also mention.
`in contrast
`to
`sghn:a'e [indjnge,
`that
`the salt erreot observed in
`unhutrered solution in tho presence of Hail H33 E sec-
`ondary rather than a primary solt effect. although the
`evidence presented In! l1nilBl-
`
`{1IH“G} fin P“ U5 Uflbuffcrcfl
`TsHLE 2. Effect of Heat
`solutions of Prooslno {from HEI.
`ID!
` ?j
`
`Time of Hunting [ninl
`
`9H [H1 F391 tE3PE?3l“T¢]
`
` o
`
`fl.3fl
`4.93
`1133
`d-BE
`gn
`4.55
`3a
`4.eo
`no
`4-43
`12$
` jj.:.na_e
`
`in min the teupersturs of
`“over the firgt
`Hos risine to 113°C.
`
`the solution
`
`In =thono]-
`ngren and fij13aen :11] have shown that
`Hater mixtures at high pH the hvdru1r=i= of erucoine
`is catalysed by both HH" and 33H5D'
`lflflfii End»
`in lb?
`letter ¢u;;_ prflfialflfi
`is converted to bsnsocaine.
`which then also reacts with UH".
`R5
`the othflnul con-
`tent
`increases at constant PH.
`thfi
`flflflV¢?3'“fl Dr PrD'
`calno to oensocsine bccnuea Drfidflfliflflflt EVEF Prflfifilflfi
`hydrolysis.
`
`Stahilisstlon Hethods
`
`thfl h?dF“1E313 “T
`tn inhibit
`Tho only effective Ho?
`procaine is to remove
`It Pro! Bflntflfil Hilh Hfltfir Hflfl
`olholi or sold. unrurtunutels.
`thin refiulta in sreat—
`iy diminished unnsthntit activity and renders the drug
`
`0018
`
`0018
`
`

`
`Tfilfl
`
`Pl:‘n::&1:I|e
`
`Eoneequentjy. ata-
`therapeutic oetiulty.
`useless for
`hliieotion methods have tnncpntrfitcd on
`the aoueoue
`solution: of procaine.
`Theee methods
`include :1} 1n-
`creasing the Efllflbillty of proeejne to get nor: of
`the
`anesthetic available in uolutiun and [3] ehjeloing the
`prnenine molecule from water
`fluhtact via m1ee11j2&—
`tioo.
`
`d|'.'I
`
`E
`
`I'‘'\.' I.'I'I
`
`
`
`3|.1|:l'artI:ll1|:El"|1fll:i-I;|l'Iolbug'-cII)‘ E5
`
`'3'
`
`'3'-5
`
`E‘.-1
`I 3
`I 3
`Molar -:onornIr.:I:n,u1 uf 5a||
`
`3.1]
`
`36
`
`1:I:|'I,'.I-
`-3-eonrent 5-oluhllieetion nr
`PI'flE=HiI1E-
`“WEE 3-
`oalne by procaine hydrochloride in water at 3n"c [12§.
`
`increase in aoluoility
`the fiflflflrenl
`FJEHTE 3 Fhflfifi
`of procaine by eonplexetinn uith prn¢a;n¢ hy¢rggh1gr—
`Ede-
`volinoti
`and fiujtnn [12] 313“ “Eat:
`that_ can.
`EIHPH lfl Gthflf =F5t¢I3 Btudfed.
`no
`inaoluble complex
`15 fflrled 33 IHE ill! ceneentrutlon is inereeeed.
`The
`
`0019
`
`0019
`
`

`
`Furqulatlehe and combinations
`
`TD1
`
`eueeeae at each a nethed in etablliaine acuaeun ere-
`eajne aulutinna 11¢; selely in the fact
`that. with
`more drug in aulutien,
`there Hill
`he mar: anesthetic
`available ntren 1!‘
`B nertlen 11-T
`il 53
`I3EE|"B1JEI3 by
`hydeelyeie.
`Aggregation uf preeaine in aqueous aclutien hae
`been studied by Farhadiah et a1.
`[13] and Jhhnfleh and
`Ludlun [1u}_
`The aggregatee were
`faced tc be email.
`with very low agzrezatieh flulhfir5-
`ht Pffifififll
`11 5!
`unclear what effect.
`if BEE.
`thii Phfiflfilfiflflfl 53? ha”?
`en stability er aqueeue eclutlehfi hf prhcaina.
`R1pp1e et a1.
`[15] have lacked at
`the ee]uh1l1:a-
`tiun |;|.f‘ prggaing by pfilyfinrhatg -ED and I!fl.'n'E 3-'|'.IIII1rII'L
`that
`at
`the PH jngrgnsgfi fro. T-fl
`te 11.c the amount of
`free prn¢a1ne 1n bath the bulk aalutien and the
`nieeilee jncreaana.
`they etate that such infcrnhticn
`can he ueeful
`in the detetllhatifln hf
`the relative
`;e;h111;y gf drug; uithin piuellee and in ereduet
`fnrsulstlca. hut nu examples are fleflt1hDEd-
`In a etuuy at prunainc hydreehlcrlde cenpleaed with
`sodium lauryl aulfate at Herein: fiflnctfllrfitififlh hf
`the
`surface aetive agent. Vila Jfltfl B1 31-
`I153 fflflflfl
`that
`as
`the gupflgeant guneantrutlea Haa
`increased frel 0
`ta it the Eu eeluee increased Erfldflfiilt
`hflfl
`thfl Tate
`ecestante for alkaline hfdrflliilfi dflflrfiflfiidu
`thflh
`Iflflifintjng ingrgfified etabjltty er
`the procaine tc
`alkaline hydrelyele.
`elegel et al. {11} have ehnwn that ernchint 13 heft
`stable in deuterium eeide Eflafll
`then in HfllET-
`T3319
`a campfire;
`the h;1r—j1[g ul peaealna ln ban and H30 at
`1fl*C.
`Even if the pn 1n age 1e eerreeted tn the "ep-
`parent“ pa,
`the ratia er
`the halt-live: shew:
`that
`the
`lnereaaad etahility in D30 13 HUI 1liF1¥ dflfi
`t0 E D5
`erreet-
`Fur axulple. celnare the pH fi.h and uh H-9
`half—liIe ratiu uf 5.e uith the pH 9.9 and DB 9.4 [He-
`carent
`pH = 9.0] ratlc cf 3.fi-
`In Eithfir E1fi¢- P?“-
`caine ie acre etahle in D30 then In H2U-
`51H$E the
`use of age 1n pharmaceutical aeellcutihhi 13 Blliht er
`hehextetent at
`this tlle.
`the practical Hfirth Of
`thlh
`ehaarvatlen reneine to he aeeh.
`
`0020
`
`0020
`
`

`
`TUE
`
`E-'J:‘fllf.'B1]'IE
`
`TABLE 3. Cnmparisun of Hate of Hydrnlyaia at Prncaine
`in Prutium Dxlda and neuteriul Dxida at an‘:
`{from Ref. 1?:
`
`Prutiun Dxidfl
`
`Dtuturjun fluid:
`
`HalfrL1Ea
`
`flaJE—L£fp
`
`P"
`
`{h}
`
`nfl
`
`in]
`
`t; flgflftk H25“
`
`B.fl
`3-5
`9.0
`9.5
`1fl.fi
`11.0
`a.n=
`
`afl.fl
`13.0
`3.5
`4.5
`3.5
`3.35
`14.nfi
`
`fl.1h
`3.9
`9.4
`9.9
`10.:
`11.1
`a.a
`
`115 n
`35.0
`13.n
`9-5
`6.25
`E-T5
`w.od
`
`3.0
`2-9
`3_u
`3.1
`1.3
`1-2
`3.9
`
`“Ratio uf half-lives at "Apparent" pH In man and PH in
`Hgfl.
`hpfl = pn + 0-4.
`“This run at 1nn*.
`dTimu for this run in in hjnutca.
`
`EEFEEEHEEE
`
`Iflth ad.], Merck and Eulpuny,
`1. Thr Merck Infler
`lnnnrnurated.
`flahuay. New Jersey. 1935. pp. 366-
`BEF.
`
`3.
`
`3.
`
`I.
`
`5-
`
`5-
`
`I. I. Hnlthurr. fllfithin. 3.. 152. 239 c1925}.
`
`E. R. Earratt, J. Pharm. ScJ_, 5], 311 11933].
`
`P. Tarp. Jcta Fharmu¢uJ.. 5. 353 qaanag.
`
`5- Bflllflflk and J.
`14.241 uaq:L
`
`5.
`
`fiunnall. Quart. J. Pharl..
`
`i- 0- HEPEHS End 5. Baron. J. Am- Pharm- As3ac..
`5|-‘--f- Efl.,-
`I--E; H-5 {I559}.
`
`0021
`
`0021
`
`

`
`References
`
`703
`
`and L. W. Busse. J. Am-
`T. Higuchi, A. Havinga,
`Pharm. Assoc.. Sci. Ed., 39, 405 (1950).
`
`T. Higuchi and L. W. Busse, J. Am. Pharm. Assoc.,
`Sci. Ed.. 39, 411 (1950).
`
`H. H. Schmid. Pharm. Acta Helv., 36, 423 (1961).
`
`R. E. Thomas and M. Woodward, Australas. J.
`Pharm., 44, S90 (1963).
`
`A. Agren and L. Nilsson. Acta Pharm. Suecica, 2,
`201 (1965).
`
`M. R. Valinoti and S. Bolton. J. Pharm. Sci.. 51,
`201 (1962).
`
`and E. R. Hammarlund,
`B. Farhadieh, N. A. Hall,
`J. Pharm. Sci., 56, 18 (1967).
`
`Johnson and D. B. Ludlum. Biachem.
`E. H.
`Pharmacol.. 18, 2675 (1969).
`
`J. Lamb,
`E. G. Ripple. D.
`Pharm. Sci-. 53, 1346 (1964).
`
`and P. W. Romlg, J.
`
`and R. C. Carro.
`J. L. Vila Jato, E. D. Aenelle,
`Chem. Phys. Appl. Surface Active Substances, Pro-
`ceedings of
`the Fourth Internatational Congress.
`1964 (4}.
`(published 1957), 2, p. 735, J. Th. 8.
`Dverbeek (Ed.), Gordon and Breach, New York.
`
`F. P. Siegel, F. D. Hiter, S. V. Susina,
`1. Blake, J. Pharm. Sci., 53, 978 (1964).
`
`and M.
`
`10.
`
`11.
`
`12.
`
`13.
`
`14.
`
`15.
`
`16.
`
`17.
`
`— Jnseph M. Conrad
`(Wisconsin)
`
`0022
`
`0022