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Pharmaceutical cocrystals

Pharmaceutical cocrystals:a comparison of sulfamerazine

with sulfamethazine

Jie Lu a,n,Yi-Ping Li a,Jing Wang a,Zhen Li a,Sohrab Rohani b,Chi-Bun Ching c

a School of Chemical&Material Engineering,Jiangnan University,Lihu Road#1800,Wuxi214122,China

b Department of Chemical and Biochemical Engineering,The University of Western Ontario,London,Ont.,Canada N6A5B9

c School of Chemical an

d Biomedical Engineering,Nanyang Technological University,Singapore637459,Singapore

a r t i c l e i n f o

Article history:

Received20June2011

Received in revised form

15August2011

Accepted12September2011

Communicated by S.Veesler

Available online17September2011

Keywords:

A1.Characterization

A1.X-ray diffraction

A2.Industrial crystallization

https://www.wendangku.net/doc/3e18828544.html,anic compounds

a b s t r a c t

Although there has been much debate about its de?nition among scientists,a cocrystal may be de?ned

as a crystalline material that consists of two or more electrically neutral molecular species held

together by non-covalent forces,and meanwhile all components are solids at room temperature.

Obviously it is great to introduce predictable structural motifs to an active pharmaceutical ingredient

(API)by design.One widely used approach to cocrystal design is based on the consideration of D p K a,

which can represent the propensity of molecular species to form a cocrystal or a salt.In this work,

p-aminobenzoic acid(PABA)was mixed with sulfamerazine(SMZ)or sulfamethazine(STH)by use of

neat cogrinding and solvent-drop cogrinding.It was found that PABA and SMZ with a D p K a of2.13

would form a binary eutectic,while PABA and STH with a larger D p K a of2.59can form a cocrystal in the

ratio of1:1.The phenomenon indicates that not only the D p K a but also the stereo-hindrance effect

(geometric?t)should be considered during the design of pharmaceutical cocrystals.

1.Introduction

A pharmaceutical cocrystal can be de?ned as a crystalline

material comprised of an active pharmaceutical ingredient(API)

and one or more unique cocrystal formers(API or non-API),which

are solids at room temperature[1].The primary difference

between cocrystals and salts is that in salts there is a proton

transfer from the acidic to the basic functionality of the crystal-

lization partner,or vise versa if applicable,whereas in cocrystals

no such transfer takes place[2].On the other hand,the main

difference between cocrystals and solvates is the physical state of

the individual pure components:if one component is in liquid-

state at room temperature,the crystals are designated as solvates;

if both components are solids at room temperature,the crystals

are designated as cocrystals[3].Till now,pharmaceutical cocrys-

tals are emerging as promising materials in drug discovery and

development,particularly in modifying drug properties such as

dissolution rate,solubility,bioavailability,stability,hygroscopi-

city,compressability and?owability[4].

Cocrystals have been prepared by melt-crystallization[5,6],

evaporation of a heteromeric solution,cogrinding,sublimation,

lyophilization[7],transformation in slurry[8],supercritical?uid-

based technique[9,10]and ultrasound assisted cocrystallization

[11,12].Among these methods,slow evaporation is the principal

approach to cocrystal’s preparation,particularly to obtain single

crystals for structure analysis,though the precipitation of indivi-

dual components instead of the desired cocrystal and formation

of undesired solvates/hydrates frequently occurs[13,14].In addi-

tion,more and more cocrystals have been synthesized by neat

cogrinding all components with a mortar and pestle or in a mixer

mill,which has also been termed‘‘solid-state cogrinding’’[15,16].

Recently a signi?cant improvement to neat cogrinding is the

solvent-drop cogrinding(liquid-assisted cogrinding,kneading)in

which the cocrystallization kinetics can be notably enhanced by

the addition of a few drops of solvent[17].

Generally cocrystal screening will occupy a lot of time and will

consume a large quantity of materials,thus it is great to introduce

predictable structural motifs to APIs by design.One widely used

approach to cocrystal design is based on consideration of p K a,as a

p K a difference of at least three units(between an acid and a base)

is required to form a salt,otherwise a cocrystal is formed[18,19].

Besides,the use of hydrogen bonding rules,synthons,graph sets

and ternary phase diagrams may assist in the design and analysis

of cocrystal systems.To date,the prediction of whether a

cocrystal will form between individual components is not yet

possible[20].

Sulfa drugs have been widely used to treat bacterial diseases in

human and veterinary medicine and to promote growth in cattle,

sheep,pigs and poultry.However,these kind of drugs can induce

different dermatological pathologies and cutaneous adverse drug

Contents lists available at SciVerse ScienceDirect

journal homepage:https://www.wendangku.net/doc/3e18828544.html,/locate/jcrysgro

Journal of Crystal Growth

doi:10.1016/j.jcrysgro.2011.09.032

n Corresponding author.Tel.:t8651085917090;fax:t8651085917763.

E-mail address:Dr.LuJie@https://www.wendangku.net/doc/3e18828544.html,(J.Lu).

Journal of Crystal Growth335(2011)110–114

reactions (CADRs)[21].Molecules in this drug class typically contain multiple hydrogen bond donor and acceptor functions,thus crystal engineering is frequently applied to improve their properties.Till now,sulfathiazole,sulfameter,sulfamethoxazole,sulfamethoxypyridazine,sulfametrole,etc.have been found to form salts (e.g.sulfamethoxazole with trimethoprim,sulfa-methoxypyridazine or sulfamethazine with 9-aminoacridine)and cocrystals (e.g.sulfamethoxypyridazine with trimethoprim,sulfameter with aspirin or 4-aminosalicylic acid)[22].

This work aimed to look into the applicability of the D p K a criterion for speci?c systems and thus to increase the under-standing of cocrystal formation.Sulfamethazine (STH)and sulfa-merazine (SMZ)(Scheme 1)were selected as model sulfa drugs for the purpose of comparison.p -Aminobenzoic acid (PABA)was selected as the cocrystal former as it can play an important role as an essential metabolite in dihydrofolic acid synthesis,which is competitively inhibited by sulfa drugs.Mechanochemical meth-ods used for the generation of the cocrystals included neat cogrinding and solvent-drop cogrinding.A systematic character-ization of STH–PABA and SMZ–PABA mixtures are conducted and compared by the use of powder X-ray diffraction,differential scanning calorimetry,thermogravimetric analysis and Raman spectroscopy.

2.Experimental 2.1.Materials

Sulfamethazine,sulfamerazine and p -aminobenzoic acid were purchased from Sigma-Aldrich (Milwaukee,WI,USA).The purity of these chemicals was 499%.All solvents with HPLC grade were also sourced from Sigma-Aldrich,and were used without further puri?cation.

2.2.Neat cogrinding

Sulfamethazine (278.3mg,1mmol)or sulfamerazine (264.3mg,1mmol)was mixed with p -aminobenzoic acid (137.1mg,1mmol)with a spatula and ground manually in a mortar and pestle for 60min,and then the resultant powders were collected for further analyses.

2.3.Solvent-drop cogrinding

1mmol sulfamethazine (or sulfamerazine)and 1mmol p -aminobenzoic acid was mixed and ground with a mortar and pestle,and 10drops of acetonitrile were added (in the extreme case,5mL acetonitrile was added to the mixture to form a slurry).The mixture was also ground for 60min,and the powder was then dried at room temperature and collected for further analyses.

2.4.Powder X-ray diffraction (PXRD)

PXRD was conducted by a MiniFlex II benchtop X-ray diffract-ometer at 30kV and 15mA with a Ni-?ltered CuK a radiation

source (l ?1.54?A)

(Rigaku,The Woodlands,TX,USA).The sam-ples were scanned from 51to 401(2y )at a scanning rate of 0.51/min.The diffractograms were processed using JADE 7.0software (Materials Data,Livermore,CA,USA).

2.5.Raman spectroscopy

Raman spectra were collected using a RamanRXN System (Kaiser Optical Systems,Ann Arbor,MI,USA)equipped with a diode laser (784.8nm)and a ?ber optic probe.Calibration was performed using a silicon standard.Ambient lighting was shut down and the samples were scanned with an exposure time of 1min in the spectral range 100to 3425cm à1at a resolution of 4cm à1.The data were processed by HoloPro TM software package.2.6.Differential scanning calorimetry (DSC)

DSC was conducted by use of a Mettler-Toledo DSC-822e differential scanning calorimeter (Mettler-Toledo,Columbus,OH,USA).Indium was used for calibration.Accurately weighed samples (6$8mg)were placed in hermetically sealed aluminum pans and scanned from 251C to 3001C at 31C/min under nitrogen purge.

2.7.Thermogravimetric analysis (TGA)

TGA was performed on a Mettler-Toledo TGA/SDTA 851e instrument.Samples (5$7mg)were heated from 251C to 4501C at a rate of 101C/min under the continuous nitrogen purge.2.8.pKa calculation

All calculated p K a values were calculated using ACD/PhysChem Suite (Advanced Chemistry Development,Toronto,Canada).

3.Results and discussion 3.1.D pKa calculation

The propensity of an acid to give up a proton and a base to accept a proton can be represented by its p K a [23].It is generally accepted that reaction of an acid with a base will be expected to form a salt if the D p K a (D p K a ?p K a base àp K a acid )is greater than 3,whereas a smaller D p K a (less than 0)will almost exclusively result in the formation of a cocrystal.When D p K a is between 0and 3,either a salt or a cocrystal will be formed [24].The calculated p K a of STH,SMZ and PABA are 7.45,6.98and 4.86,respectively.The D p K a between SMZ and PABA is thus 2.13while that between STH and PABA is 2.59.From previous studies [22]and the calculation for D p K a,the mixtures of either SMZ–PABA or STH–PABA are speculated to form salts or

cocrystals.

Scheme 1.Molecular structures of sulfamerazine (SMZ),sulfamethazine (STH)and p -aminobenzoic acid (PABA).

J.Lu et al./Journal of Crystal Growth 335(2011)110–114

111

3.2.PXRD

The results of PXRD analyses for the products from different preparation methods are shown in Figs.1and2.As shown in Fig.1,the diffractograms of the products from neat cogrinding and solvent-drop cogrinding SMZ with PABA are the same as that of the product from simply blending.This indicates that cogrind-ing SMZ with PABA does not result in a new solid form.

By contrast,as shown in Fig.2,the diffractograms of the products from neat cogrinding and solvent-drop cogrinding STH with PABA are different with that of the product from simply blending.As for neat cogrinding,the intensity of the characteristic peaks of STH at9.31was decreased and at9.51was increased; meanwhile a new peak at20.61occurred,which indicated that a new phase was formed during the neat grinding of STH and PABA. On the other hand,when solvent-drop cogrinding was employed, the PXRD diffractogram of the product was totally different with those by neat cogrinding and simply blending.From the compar-ison of peaks around20.61,we think the new phase generated in the neat cogrinding for60min shall be incomplete cocrystals. Furthermore,when the solvent,which can totally or partially dissolve the original components was added to the cogrinding process,the opportunities for molecular collisions will be increased,and the relaxation of solute molecules shall facilitate the effective interactions between them,leading to an increased rate of cocrystallization[25].

3.3.DSC

DSC analyses for the resulting powders of blending,neat cogrinding and solvent-drop cogrinding are shown in Figs.3and4. Thermogravimetric analysis demonstrated that there was no loss of mass prior to decomposition for all samples.As shown in Fig.3,the melting points of SMZ and PABA are236.81C and 188.91C,respectively.An endothermal peak at about1641C occurs for all mixtures.Based on the results of PXRD,the endothermal peak at about1641C indicates that SMZ and PABA can form a eutectic instead of a new compound.As shown in Fig.4,a melting endotherm at about216.41C,which differs from the melting points of either STH(199.21C)or PABA (188.91C)occurred for all cogrinding powders.This indicated that a new phase was formed between STH and PABA during cogrinding.Besides,the DSC results showed that heating of the blending mixture can also result in the formation of a new solid form(the lower melting point213.11C is due to residual STH or PABA after the formation of the new solid form during

heating).

Fig.1.Powder X-ray diffraction patterns of SMZ–PABA

system.

Fig.2.Powder X-ray diffraction patterns of STH–PABA

system.

Fig.3.DSC analyses of the resulting powders of SMZ and PABA after blending,

neat cogrinding and solvent-drop

cogrinding.

Fig.4.DSC analyses of the resulting powders of STH and PABA after blending,neat

cogrinding and solvent-drop cogrinding.

J.Lu et al./Journal of Crystal Growth335(2011)110–114

112

3.4.Raman spectroscopy

As single crystals are not available for determining exact structures,the evaluation of whether a new phase occurs or not and of the extent of proton transfer in the new phase can be carried out by spectroscopic analysis using vibrational spectro-scopies.In this work,Raman spectroscopic data were utilized for the above evaluation.Figs.5and 6are Raman spectra in the region of 1200to 1700cm à1of SMZ–PABA system and STH–PABA system,respectively.

As shown in Fig.5,Raman spectra of the resulting powders of blending,neat cogrinding and solvent-drop cogrinding are almost identical.By contrast,as shown in Fig.6,the spectrum of blending is almost same as that of neat cogrinding except shifts between 1593cm à1and 1600cm à1,but is quite different with that of solvent-drop cogrinding,which can suggest that a new solid formed during solvent-drop cogrinding STH and PABA.

The Raman spectrum for pure PABA in the starting material has a band at 613cm à1(data not shown)corresponding to out-of-plane bending of carbonyl (C ?O).When cocrystallizing with STH,the band was shifted to 618cm à1,suggesting the carbonyl (C ?O)has participated in the hydrogen bonding [26].On the other hand,as shown in Fig.6,the Raman spectrum for pure sulfamethazine in the starting material has bands at 1342cm à1

and 1637cm à1,corresponding to N–H deformation and NH 2bending,respectively [27].During the cocrystallization with PABA,these bands in the new phase were shifted to 1359cm à1and 1627cm à1,respectively.These slight band shifts indicate that a cocrystal was formed as the bands should be shifted by 30to 40cm à1if a salt is formed [28].The increase in the in-plane N–H deformation frequency of STH from 1342cm à1to 1359cm à1indicates that the sulfa N–H (linked to sulfonyl)is participating in the hydrogen bonding.The structure of STH–PABA cocrystal is shown in Fig.7.3.5.SMZ and STH

As described in above,the D p K a between SMZ and PABA is 2.13,which is lower than that between STH and PABA;however,the latter with a larger D p K a can form a cocrystal while the former with a lower D p K a can form neither a salt nor a cocrystal.This is suggesting that the value of D p K a between a base and an acid can not fully predict the tendency and the extent of the reaction.In sulfamerazine both amino protons bond to sulfonyl oxygens and the amido proton bonds to a heterocyclic nitrogen,whereas in sulfamethazine both amino protons bond to hetero-cyclic nitrogens and the amido proton bonds to a sulfonyl oxygen.The difference in the stereo-hindrance effect (geometric ?t)caused by above intramolecular hydrogen bonding seems to be responsible for their different reactivity with PABA [29].

4.Conclusion

This study has compared the cocrystallization behaviors of SMZ and STH with PABA.PABA and SMZ with a lower D p K a formed a binary eutectic,while PABA and STH with a larger D p K a formed a cocrystal.The results demonstrate that pharmaceutical cocrystals can be synthesized by cogrinding,especially solvent-drop cogrinding.The addition of small amount of solvent to the cogrinding process can greatly increase the rate of cocrystalliza-tion.Furthermore,the design of cocrystals can not be only based on the consideration of p K a,such other factors as stereo-hin-drance effect,intramolecular hydrogen bonding,etc should be taken into account.

Acknowledgments

We acknowledge the ?nancial supports of the National Natural Science Foundation of China (Nos.21176102and 21176215),the Scienti?c Research Foundation for Returned Chinese Scholars and the Fundamental Research Funds for the Central Universities (No.

JUSRP30904).

Fig.5.Raman spectra in the region of 1200to 1700cm à1of SMZ,PABA,mixtures after blending,neat cogrinding and solvent-drop

cogrinding.

Fig.6.Raman spectra in the region of 1200to 1700cm à1of STH,PABA,mixtures after blending,neat cogrinding and solvent-drop

cogrinding.

Fig.7.Structure of the cocrystal formed between STH and PABA.

J.Lu et al./Journal of Crystal Growth 335(2011)110–114

113

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