pharmaceutical salts and cocrystals involving amino acids a brief structural overview of the state...

7232019 Pharmaceutical Salts and Cocrystals Involving Amino Acids a Brief Structural Overview of the State of Art 2014 Eurhellip

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Mini-review

Pharmaceutical salts and cocrystals involving amino acids A brief structural overview of the state-of-art

Anaeumllle Tilborg Bernadette Norberg Johan Wouters

Uniteacute de Chimie Physique Theacuteorique et Structurale Dept Chemistry University of Namur 61 Rue de Bruxelles B-5000 Namur Belgium

a r t i c l e i n f o

Article history

Received 24 May 2013

Received in revised form

22 November 2013

Accepted 27 November 2013

Available online 18 January 2014

Keywords

Therapeutic salt

Pharmaceutical cocrystal

Amino acids

Active pharmaceutical ingredient (API)

Drug substance

Coformer

Patent rights

a b s t r a c t

Sali1047297cation of new drug substances in order to improve physico-chemical or solid-state properties (eg

dissolution rate or solubility appropriate workup process storage for further industrial and marketing

development) is a well-accepted procedure Amino acids like aspartic acid lysine or arginine take a great

part in this process and are implicated in several different formulations of therapeutic agent families

including antibiotics (amoxicillin from beta lactam class or cephalexin from cephalosporin class) NSAIDs

(ketoprofen ibuprofen and naproxen from profen family acetylsalicylic acid) or antiarrhythmic agents

(eg ajmaline) Even if more than a half of known pharmaceutical molecules possess a sali1047297able moiety

what can be done for new potential drug entity that cannot be improved by transformation into a salt In

this context after a brief review of pharmaceutical salts on the market and the implication of amino acids

in these formulations we focus on the advantage of using amino acids even when the target compound

is not sali1047297able by exploiting their zwitterionic potentialities for cocrystal edi1047297cation We summarize

here a series of new examples coming from literature to support the advantages of broadening the

application of amino acids in formulation for new drug substances improvement research for non-

sali1047297able molecules

2013 Elsevier Masson SAS All rights reserved

1 Salts

11 Why using salt forms in drugs substances

Since modern medication research has produced valuable drug

compounds the problem of appropriate administration of these

molecules has been posed In fact even if the compound is

considered as biologically ef 1047297cient after a series of molecular tests

its physico-chemical and solid-state lacks of performance can break

the preformulation development Since a while the main pathway

for more than an estimated half of all concerned potential thera-

peutic molecules (ie those possessing a (de)protonation center)

has been to turn them into a properly-administrated salt with aconvenient salt agent [1e3]

Salt formulation offers great convenience for drug administra-

tion essentially by providing for concerned molecules an improved

physico-chemical 1047297tted pattern for further application If one looks

carefully through this improvement the main constituent of the

promotion lies in the increase of dissolution rate and solubility in

water In fact it seems legit that an ionizable species like a salt will

be more soluble inwaterand thus afford a betterchance of reaching

the biological target place regardless of the required administra-

tion pathway (eg intravenous oral ) [145]

But other objectives can also be achieved by forming a salt First

pure solid-state considerations are to be taken into account more

reliable products chemically stable and easy to recrystallize and

purify formulations can be obtained by this way [1] Polymorphism

issues for some compounds can be avoided In the synthetic devel-

opment process working with salts can be an economic means to

separate an intermediate from side products Similarly like for solu-

bility properties compatibility with selected excipients biological

performanceand safety concerns can alsobe modi1047297edby sali1047297cation

By all these modi1047297cations a new salt formulation certainly opens anew 1047297eld of therapeutic applications Moreover it can valuably ap-

peal for an extension of patent rights approval will be simpli1047297ed

because of the already stating knowledge of the effects of the newly

drug form with background coming from the early product [3e5]

12 Which salt agent can be selected to form a reliable

pharmaceutical salt

A lot of aspects have to be considered when a salt formation is

envisaged for a drug development In fact so many additional costs

will be engaged if the salt agent proves to be non-suitable for the

Corresponding author

E-mail addresses anaelletilborgunamurbe (A Tilborg) bernadettenorberg

unamurbe (B Norberg) johanwoutersunamurbe (J Wouters)

Contents lists available at ScienceDirect

European Journal of Medicinal Chemistry

j o u r n a l h o m e p a g e h t t p w w w e l se v i e r c o m l o c a t e ej m e c h

0223-5234$ e see front matter 2013 Elsevier Masson SAS All rights reserved

httpdxdoiorg101016jejmech201311045

European Journal of Medicinal Chemistry 74 (2014) 411e426



application that a careful decision implicating all facets of the

problem is mandatory for the proper salt development process

In this context amino acids (Fig 1 [6abcd]) seem to be a

valuable choice as suitable salt partners They are GRAS com-

pounds with a very low toxicity easily reachable in terms of

implementation in the process and non-expensive They are

already implicated in a variety of developed and marketed phar-

maceutical salts A brief overview of the place of amino acids in

chemical and pharmaceutical sciences follows in the next section

2 Amino acids

21 Overview of amino acids in chemical and pharmaceutical

sciences

Before being suitable salt counterions for pharmaceutical

agents amino acids (Fig 1) and their derivatives can be found in

a variety of therapeutic compounds but also in daily-life

products

The most common example to be cited is phenylalanine and

aspartic acid which are the two constituents of aspartame [7]

(Scheme 1 pKa frac14 325 (acidic group) pKa frac14 812 (basic group)

predicted values from Pallas [8]) For derivatives a well-known

case is acetylcysteine [9] e directly derived from cysteine e used

as an antidote in case of acetaminophen overdose and as anti-

obsessive compulsive disorder drug (pKa frac14 325 (acidic group)

pKa frac14 1074 (basic group) predicted values from Pallas [8]) N6-

Cbz-L -lysine benzyl ester hydrochloride a derivative of lysine is

used during preparation of antithrombotic agents [10] (Scheme 1)

From a more organic point of view one can cite leucine isoleucine

valine alanine phenylalanine methionine and some derivatives as

norvaline norleucine or 2-aminobutyric acid that are crystallized

together to study chiral aggregation [11e14] Alanine phenylala-

nine tyrosine and tryptophane are used as pharmaceutical

Fig1 20 natural L -amino acids developed formulas (at physiological pH) three-letter and one-letter peptic codes molecular weight (MW) isoelectric point (pI) hydropathy index

(Hydropathy) [6b] occurrence in proteins in (occurrence) [6c] and water solubility (g100 mL at 25

C solubility) [6d]

A Tilborg et al European Journal of Medicinal Chemistry 74 (2014) 411e426 412



organogel gelators after addition with lauryol stearoyl or behe-

neoyl esters [15]

Some amino acids more speci1047297cally biological essential amino

acids (isoleucine leucine lysine methionine phenylalanine thre-

onine tryptophan and valine) ie those that cannot be produced by

the human body from other precursors are also marketed alone or

combined with other amino acids glucose or lipid solutions for

parenteral nutrition among patients in reanimation from anes-

thesia [16] Amino acids especially arginine and proline are also

regarded in the 1047297eld of nutriceuticals in the same way than vitamin

C or E carotene or coenzyme Q10 [17]

For this review bibliographic searches have been performed in

the crystallographic Cambridge Structural Database [18] and withthe help of SciFinder the web-interactive CAS database [19] The

classical amino acids have been thoroughly searched and results

are assembled in Fig 2 At 1047297rst look it can be seen that the number

of crystal structures implying natural amino acids are relatively

high in comparison with hit numbers in SciFinder This observation

has to be slightly modi1047297ed by considering the research terms in

SciFinder the number of results which have been extracted stands

for ldquoamino acid thorn salt rdquo or ldquoamino acid thorn cocrystalrdquo termsand not for

ldquoamino acidsrdquo alone In all cases these results seem to us surpris-

ingly low in view of the obvious advantages for amino acids as salts

counterions or cocrystal formers

To better apprehendthe complexity of these ions we have focused

our attentionon the overall charges (thornthornthornthornfrac14 zwitterion)

observed for different pH ranges for natural amino acids This can

potentially explain their noticed limited use in pharmaceutical solid-

state sciences

At physiological pH (74 Figs 1 and 3) even if natural amino

acids are all charged not all amino acids are in a zwitterionic state

(thorn) It obviously depends on the side chain (SC) which can be

acidic (Asp Glu Cys Tyr) or basic (His Lys Arg) and stronglymodi1047297es the behavior of the moleculeThis very simple observation

will be of great importance for further edi1047297cation of new multi-

component products implying amino acids such as salts or

cocrystals

With all these considerations in mind it has been demonstrated

before that amino acids can be a suitable choice as proper salt

counterions and cocrystal formers A brief outline of these salts

Scheme 1 Developed formulas of selected therapeutic agents existing under salt form with amino acid salt partners and examples of new organogels from amino acid derivatives

[15]

Fig 2 Results (on the left) from bibliographic researches in CSD and SciFinder databases for amino acids (salts or cocrystals for SciFinder entry) Hit numbers for Arg and Lys in

SciFinder salts and for Phe Ala and Gly for CSD hits have been divided by ten for clarity Results (on the right) from bibliographic researches in SciFinder for amino acid salts or

cocrystals for each year since 1990 (until 2012)

A Tilborg e t al European Journal of Medicinal Chemistry 74 (2014) 411e426 413



follows in the next section and a particular attentionwill be paid to

cocrystals implying amino acids in the Section 3

22 Pharmaceutical salts implying amino acids as counterions

Several of the 20 natural amino acids can be classi1047297ed as anionic

(acidic behavior) or cationic (basic behavior) under physiological

conditions At 1047297rst L -aspartic acid (aspartate) and L -glutamic acid

(glutamate) are the prime candidates in anionic category They

appear in a series of salt crystal structures like for aspartate with L -

ornithine [6] (CAPRAM [21]) guanidine [22] (DUFDOX10 [23]) or

tetracycline [24] (ZZZJWU [25]) For glutamate combinations have

been reported and characterized with guanidine (KABKEF [26])

110-diazonia-18-crown-6 [27] (UCAJEN [28]) 2-methylimidazole

[29] (TULZEF [30]) inosine-50-monophosphate (QUSMIA [31]) or

putrescine [32] (VOWHOE [33] and VOWHUK [34]) (Fig 4)Aspartate and glutamate can also be combined with other amino

acidssuch as aspartatewith arginine (DUSLUY [35] SITBOM [36] or

NAGLYB10 [37]) and lysine (JAVSEE [38]) or glutamate and argi-

nine (ARGGLU10 [39] DUSMAF [35] and KEMYUW [40]) and lysine

(JAVSII [38]) (Fig 5) Some of the reported salts are hydrates L -

ornithine and L -aspartate (CAPRAM) is a hemihydrate L -aspartic

acid and tetracycline sulfate (ZZZJWU) is a decahydrate L -gluta-

mate and 2-methylimidazole (TULZEF) is a hydrate and L -gluta-

mate and inosine-50-monophosphate (QUSMIA) is an

undecahydrate For combinations with other amino acids L -lysine

and D-aspartate (JAVSEE) form a monohydrate like L -glutamate and

L -arginine (ARGGLU10) or D-glutamate and L -arginine (KEMYUW)

D-glutamate and L -arginine (DUSMAF) form a trihydrate If one

examine in details the structural organization in some selectedsalts implying aspartate or glutamate three main schemes of

crystalline layouts including the selected amino acid can be

distinguished the 1047297rst implies hydrogen-bonding interactions

with ldquomain-chainrdquo (MC) atoms (carboxylic acid and amine group

supported by the chiral Ca carbon) the second hydrogen bonds

implying ldquoside-chainrdquo (SC) atoms (functional group appearing on

the substitute chain which characterizes each amino acid) and the

third e mostly for amino acid combinations but also in other cases

e ldquoheterordquo H-bonding interactions only between ldquomain-chainrdquo

atoms and ldquoside-chainrdquo atoms (MCSC) Additional H-bonds

including a water molecule and the amino acid (or the other

molecule in the structure) are also present if the structure is a

hydrate L -aspartate L -ornithine salt structure (CAPRAM Fig 4) is a

perfect example of those different interactions main-chain H-

bonds are highlighted in black side-chain H-bonds in gray and

hetero main-chainside-chain H-bonds in black dotted on Fig 4In the salt structure implying L -aspartate and guanidinium the

MC and SC network is more ldquolayeredrdquo as for structures implying L -

glutamate For the hydrated salt with L -aspartate and 2-

methylimidazole the three different H-bond layouts are inserted

between each other and the L -glutamate guanidinium salt possess

a staggered-row network of main-chain and side-chain in-

teractions Noteworthy it seems important to notice at this point

that all interactions can be considered as charge-assisted H-bonds1

due to the (de)protonation state of the amino acid and of the charge

of the counterion in the salt structure

If one applies the same structural categorization for combina-

tions of anionic amino acid (aspartate and glutamate) with another

amino acid a more cluster-localized MC and SC network is

observed for the salt between L -aspartate and L -argininium and

layered-like MC and SC networks are observed for the salt between

D-glutamate and L -argininium (with water-mediated hydrogen

bonds) (Fig 5)

The cationic natural amino acids category classically contains L -

lysine L -arginine and L -histidine But it seems appropriate to

slightly shade this classi1047297cation at physiological pH His

(pKa frac14 622) is a zwitterion while Lys (pKa frac14 1062) and Arg

(pKa frac14 1248) carry an overall positive charge (Fig 3) Classi1047297cation

as ldquobasicrdquo amino acids of these three ones only relies on their

cationic form This is obviously not the case for His But for clarity

His will remain assimilated to the cationic category with Lys and

Arg in the following sections

For lysine a series of crystal structures implying an API or a

research active molecule have been obtained and retrieved from

CSD salts with hemipimelate [43] or panthotenate [44] (AKOGAI[45] and BACWUX10 [46] respectively) with picrate [47] calixar-

ene2 [48] or orange G [49] (TEFMEW [50] WIXSOL [51] or ZUCQAP

[52] respectively) (Fig 6) Other salt forms exist One can mention

usage of lysine with different families of therapeutic agents for

analgesic or anti-in1047298ammatory effects lysine is combined with

acetylsalicylic acid (pKa frac14 349 Merck Index 1983 [53]) (Aspeacutegic

Kardeacutegic) ibuprofen (pKa frac14 491 [54]) (PerdoFemina Neo-

profen) or ketoprofen (pKa frac14 491 [55]) and naproxen (pKa frac14 406

Fig 3 Protonation pH ranges for the 20 natural amino acids underlying the overall charges of the compounds (thornthorn thorn thornfrac14 zwitterion thorn(thorn)) for cationic amino acid (SC

stands for Side-Chain group) [820] pKa values delimit the zones

1 Hydrogen bonds can be mediated by charge assistance if one of the partners

carries a full charge Such behavior is well-documented for hydrogen bonds

implying oxygen moieties [4142]2

5101520-Tetrakis( p-sulfonato)-25262728-tetrahydroxycalix(4)arene




predicted value from Pallas [8]) from the same NSAIDs family

Lysine can also be combined with antibiotics amoxicillin from b-

lactam series (pKa frac14 280 (acidic group) pKa frac14 743 (basic group)

predicted values from Pallas [8]) chloramphenicol as broad-

spectrum bacteriostatic antimicrobial (discontinued status indi-cated by FDA but still employed in developing countries [56]

pKa frac14 961 [57]) benzylpenicilloyl derivative for Pre-Pen skin tests

before use of penicillin (pKa frac14 274 Merck Index 1996 [58]) [59] or

cephalexin (pKa frac14 530 (acidic group) pKa frac14 731 (basic group)

Merck Index 1996 [58]) from cephalosporin category It is also used

with theophylline (pKa frac14 881 [60]) for respiratory disorders

(Scheme 2)

MC and SC H-bond networks (Fig 6) are also characteristic for

each salt in the case of L -lysine and picrate the three networks are

multi-dimensional cross-layered and for hydrated salt of DL -lysine

and benzenesulfonatederivative the two MC and SC networks arein

Arginine forms salts with different classes of therapeutic agents

One could cite bicalutamide (pKa frac14 1195 predicted values from

Pallas

[8]) [61] an anti-androgen used in treatment of prostate

cancer 1047298uoroquinolones or benzoquinolines [62] an antibacterial

and antiviral agent family acetylsalicylic acid [63] for NSAIDs family

perindropil (pKa frac14 379 predicted values from Pallas [8]) [64] an

arterial hypotensive agent or ragaglitazar (pKa frac14 427 predicted

values from Pallas

[8]) [65] (UHUCUV [66]) to restore insulinsensitivity among diabetic patients Arginine also appears in combi-

nation with nitrofurantoin [67] (ORUXEF [68]) (Scheme 3 and Fig 7)

In the L -argininium ragaglitazar complex the MC and SC net-

works are deeply imbricated due to the conformation of the L -

argininium presenting its main-chain and side-chain H-bond

moieties in the same direction and forming a row-stacking of

argininium ions to which ragaglitazar entities are linked This kind

of arrangement can be found in different salt and cocrystal struc-

tures implying amino acid like L -proline [6970] as discussed

further in this work In the L -argininium and nitrofurantoine

(pKa frac14 72 [55]) salt conformation of L -argininium leads to another

lattice MC and SC networks are more separated and form ldquolayersrdquo

of H-bond interactions with the counterion H-bonds with water

molecules further involve the main-chain atoms of the amino acid

Fig 4 Molecular structures for selected salts including aspartate and glutamate (Main-chain) (MC) H-bonding interactions in black side-chain (and hydrate interactions) (SC) in

gray and hetero main-chainside-chain H-bonds (MCSC) in black dotted On top of global structure examples of MC SC or MCSC H-bonding interactions in the network are

highlighted in black gray or black dotted

Fig 5 Selected molecular structures for salts including two amino acids (one acidic aspartate or glutamate) (MC and SC interactions highlighted in black or gray respectively)




Fig 6 Molecular structures for pharmaceutical salts including lysine (main-chain side-chain and hetero main-chainside-chain interactions highlighted in black gray and black

dotted respectively)

Scheme 2 Structures of therapeutic agents existing under salt form with lysine

Scheme 3 Structures of therapeutic agents existing under salt form with arginine




Histidine forms salts with a series of organic acids One can cite

tartric acid and tartaric acid (IZAJUO [71] IXAVEI [71] OJEPIC [72]

YAGKAT [71] or UKORUH [73]) other anionic amino acids like

aspartate (LHLASP10 [74]) common salt counterions in the phar-

maceutical 1047297eld (maleic acid (XADTIF [75]) glycolate (TEVJUZ [76]

or TEJWAG [76]) or trimesate (DLHTMS [77])) or organic dyes

(Orange G (ZUCQOD [52] and ZUCQUJ [52]))

In the tartrate salt with D-histidinium the MC SC and MCSC H-

bond layouts are inserted between each other and glycolate DL -

histidinium salt possesses a staggered-row network of MC SC and

MCSC H-bond interactions (Fig 8)

Arg Lys and His amino acids can also be found under salt forms

with acidic amino acids lysine with aspartate or glutamate (JAVSEE

[38] JAVSII [38] and LYSASP [78] entries respectively) and arginine

with glutamate and aspartate (ARGGLU10 [39] KEMYUW [40]

SITBIG [36] NAGLYB10 [37] and SITBOM [36]) (Fig 9)

Fig 7 Selected molecular structures for pharmaceutical salts including arginine amino acid (MC and SC interactions for selected amino acid highlighted in black and gray

respectively)

Fig 8 Molecular structure of a selected pharmaceutical histidinium salt (MC SC and

MCSC interactions for selected amino acid highlighted in black gray and black dotted

respectively)

Fig 9 Selected molecular structure for salt including two amino acids (MC SC and

MCSC interactions highlighted in black gray and black dotted respectively)

Scheme 4 Developed formulas of metadoxine used with proline

Table 1Small amino acids used as zwitterionic coformers in cocrystals and their relative

crystalline structures if available (Selected CSD structures in 1047297gure beyond table)

Amino

acid

Sci Fin der r esults CSD stru ctures

Gly Glyglutaric acid [90]

GlyNaNO3 [91]

Glyglutaric acida [90]

GlyGly nitrateb [91]

Glytrimesic acid monohydratec [92]

GlyGly fumarate monohydrated [93]

GlyGly perchloratee [94]

GlyGly tetra1047298uoroboratef [94]

GlyGly sulfateg [95]

Gly35-dihydroxybenzoic acid

monohydrateh [96]

Ala L -AlaValAlaH2O [98] L -AlaR-2-(Phenoxy)propionic

acidi [97]

L -Alaclathrate j [99]

L -AlaS-mandelic acidk [100]

L -AlaL -Ala nitratel [101]

L -AlaR-mandelic acid

hemihydratem [102]

a AWIHOEb DGLYCN01c GLYTMSd GOLZIRe QURQOKf QURQUQ

g TGLYSU11h UCEMEVi BEYVAD j HOSLIL ((thorn)-(18-crown-6)-231112-tetracarboxylic acid)k IROVAMl OCAVIX

m

XUGMER




In the L -lysinium and L -aspartate salts the MC and SCMCSC

networks are more aligned than for salts between L -argininium and

L -aspartate where MC and SC networks are more imbricated and

cluster-localized (Fig 9)

Nucleophilic (cysteine serine) hydrophobic (methionine pro-

line) or aromatic amino acids (tryptophane phenylalanine) are also

employed as salt counterions with pharmaceutical compounds For

example proline is used with metadoxine (Scheme 4 pKa frac14 867

predicted value from Pallas [8]) [79] employed for patients with

liver disorders and cysteine and methionine are combined [80] as

antiseborrhoeic agent

3 Cocrystals

31 What can be done with new potential therapeutic agents if they

are not sali 1047297able

Potential promising molecules which do not possess appro-

priate solid-state and solubility properties and cannot be trans-

formed into salts were in the past erased from development

processes to avoid costly readjustments If these molecules are not

sali1047297able an elegant way of employing them even if their structures

are not optimal is using cocrystallization Pharmaceutical cocrys-

tallization is de1047297ned as the formation of a ldquococrystalrdquo a combina-

tion of an API and a cocrystallizing agent or coformer very often an

organic molecule safe for pharmaceutical utilization (eg GRAScompounds from Food and Drug Administration (FDA) [81]) As a

matter of fact a panel of existing de1047297nitions in the specialized

literature gives different elements on the concept of cocrystal but it

stays dif 1047297cult to obtain a concise general de1047297nition also because of

the overlap with other well-known solid forms principally salts An

attempt has been made by several authors in the research 1047297eld [82]

especially to better distinguish the concept of cocrystal from more

classical salt formation The FDA also recently provides in guidance

for industry a regulatory classi1047297cation of pharmaceutical cocrystals

Fig 10 Selected cocrystal crystal structures implying small amino acids glycine or alanine (MC interactions for selected amino acid highlighted in black)

Table 2

Nucleophilic amino acids used as zwitterionic coformers in cocrystals and their

relative crystalline structures if available

Amino

acid

SciFinder results CSD structures

Ser L -SerPyridine-24-dicarboxylic

acid [103]

L -SerPyridine-24-dicarboxylic

acida [103]

L -SerL -Ser phosphate

monohydrateb [104]

Thr L -Thrclathrate pentahydratec [98]

L -ThrL -all-Thrd [105]

Cys L -CysS-mandelic acide [106]

L -CysR-mandelic acidf [106]

a SITCUUb EYOQOYc HOSMUY ((thorn)-(18-crown-6)-231112-tetracarboxylic acid (thorn)-(18-crown-6)-

2311-tricarboxylic acid-12-carboxylate clathrate pentahydrate)d AETHREe LAWKIEf RAZPUE

Fig 11 Selected cocrystal crystal structures implying nucleophilic amino acids serine or cysteine (MC and MCSC interactions for selected amino acid highlighted in black and black





taking into account the notion of pKa difference between the spe-

cies involved in the structure (Salt-Cocrystal Continuum Model [83])In this context our personal de1047297nition of a cocrystal borrows

different elements from the existing de1047297nitions especially from

Ref [84] a cocrystal is a multicomponentcrystal in which at least two

components are solid under ambient conditions (to distinguish them

from pure solvates) These components co-exist as a stoichiometric

ratio of a target molecule or ion and a neutral molecular cocrystal

former(s) (to introduce the idea of zwitterionic compounds in

cocrystals) bound together through non-covalent interactions often

including hydrogen bonding (Hydrogen bonds are the most impor-

tant intermolecular interactions playing a role in the structuration

of a cocrystal even if they are not the only ones For example

metallic coordination bonding could be considered as the principal

interactions for metallic salt or metallic coordination complexes

linked to a drug molecule also called sometimes ionic cocrystals

[85]) Cocrystallization is one of the emergent promising ap-

proaches in the 1047297eld of pharmaceutical solid-state chemistry

[586e89] Indeed it is unnecessary to highlight all the advantages

of using cocrystallization as a mean to optimize physico-chemical

properties [88] In this context amino acids could be of 1047297rst in-

terest in formation of new multicomponent chemical entities

Moreover their zwitterionic potentialities could be used to form a

new subclass of cocrystals zwitterionic cocrystals These latter can

be represented as a combination of a zwitterionic compound (the

coformer essentially) and the cocrystallized molecule of interest

Several examples already exist in the solid-state1047297eld and for some

of them they comprise a therapeutic molecule

An exhaustive list of cocrystals implying amino acids based on

structural research in CSD [18] and literature scanning with the

Table 3

Hydrophobic amino acids used as zwitterionic coformers in cocrystals and their


Amino

acid

SciFind er resu lts CSD str uctur es

Val L -ValD-2-aminobutanoic

acid [13]

L -Valfumaric acid [109]

D-ValL -Leua [13]

L -ValD-2-aminobutanoic acidb [13]

L -ValD-norvalinec [13]

L -ValD-Metd

[13]DL -Valsuccinic acide [107]

D-ValL -Ilef [11]

L -ValR-2-Phenoxypropionic acidg

[108]

L -ValD-norleucineh [11]

DL -Valfumaric acidi [109]

DL -ValDL -Val picrate j [110]

L -ValL -Val perchlorate monohydratek

[111]

D-ValL -Phel [112]

L -Valfumaric acidm [113]

Leu L -LeuD-norleucine [115] L -LeuD-2-aminobutanoic acidn [13]

L -LeuD-norvalineo [13]

L -LeuD-Metp [13]

D-LeuL -Ileq [11]

L -LeuL -Leur [114]

L -LeuD-norleucines [12]

D-LeuL -Phet [14]

D-LeuL -allo-Ileu [115]

Ile L -IleD-Ala [11]

L -IleD-norvaline [11]

L -IleD-norleucine [11]

L -IleD-Met [11]

L -IleL -Phe [14]

L -IleD-allo-Ile [116]

L -IleD-Alav [11]

L -IleD-aminobutyric acidw [11]

L -IleD-norvalinex [11]

L -IleD-norleuciney [11]

L -IleD-Metz [11]

D-IleL -Pheaa [14]

L -IleD-allo-Ileab [116]

Met D-MetR-mandelate R-mandelic acidac

[117]

L -MetD-norleucinead [12]

D-MetL -Pheae [14]

D-MetL -Norvalineaf [115]

L -MetL -Met perchlorate

monohydrateag [118]

DL -MetDL -Met picrateah [119]

Pro L -Propyranetriolderivativeai [133]

L -Pro11-Dicyano-2-(4-

hydroxyphenyl)-ethene

[126]

L -Pro4-

ethoxyphenylboronic acid

[127]

L -Pronitrofurantoin [134]

L -ProMnCl2$H2O [135ab]

L -ProLiCl [136]

DL -Prohemisuccinic acidaj [120]L -ProL -Pro tetra1047298uoroborateak [121]

L -Pro monohydrate4-Aminobenzoic

acidal [122]

L -Pro methanolatethiourea

derivativeam [123]

L -Pro(11R12R)-(thorn)-910-Dihydro-

910-ethanoanthracene-1112-

dicarboxylic acidan [124]

L -ProL -proline perchlorateao [125]


hydroxyphenyl)etheneap [126]

L -Pro4-ethoxyphenylboronic acidaq

[127]

L -ProL -Pro nitratear [128]

L -Probis(7788-

tetracyanoquinodimethanide)

bis(tetracyanoquinodimethane)as

[129]L -Pro4-(246-Tri-isopropyl-benzoyl)

benzoic acidat [130]

L -ProPentacyclodecane-25-

dicarboxylic acidau [131]

L -Pro25-dihydroxybenzoic acidav

[132]

a BERPETb BERQAQc BERQEUd BERQIYe EWOZIZf FITMEA

g GALPITh GOLVUYi HAGYEU j PAHCIL

k QOQWEYl SONCED

m VIKLUXn BERNANo BERNERp BERNIVq FITNIFr FOGYEGs GOLWEGt

POVYUVu URODELv FITHIZ

w FITJATx FITJEXy FITLEZz FITLID

aa POVZACab XADVEDac FONJAUad GOLVOSae POVYOPaf URODIP

ag WOYVIPah XAZNAOai (2S 3R4R5S 6R)-2-(3-(4-ethylbenzyl)-(phenyl)-6-hydroxymethyl)-tetrahydro-

2H -pyran-345-triolaj LABZUJ

ak CADKOJal CIDBOH

am DUKJUP ((SRRRSS)-1-[35-bis(tri1047298uoromethyl)phenyl]-3-[(5-ethenyl-1-

azabicyclo[222]octan-2-yl)(6-methoxyquinolin-4-yl)methyl] thiourea)an GIVROSao IDINAKap IHUMAZaq KECJIMar LUDFOFas OLIZALat POKHAY10

au VESCUSav ZEZHIV




help of SciFinder program [19] is developed here in Tables 1e6 and

Figs 10e15

Small amino acids (Table 1) are implied in diverse cocrystal

structures under their zwitterionic forms in combination with a

variety of neutral coformers including GRAS or GRAS-like acids

(protonated glutaric acid (AWIHOE) or fumaric acid (GOLZIR)) or

clathrate structures (HOSLIL) Combined searches with SciFinderand in the CSD are necessary in thiscasee even more than for ldquosalts

with amino acidsrdquo searches- because of the classi1047297cation itself of

the ldquococrystalrdquo term in SciFinder some structures that are in our

structural sense classical salts can be retrieved under the ldquococ-

rystalrdquo category and the opposite can occur too So we decided to

also take in consideration CSD hits in our literature scanning In

fact some of the cocrystal structures found in CSD are not referred

with a simple ldquoamino acidrdquo thorn cocrystal search term This is why

(proven once more with this single example) it is important to

undertake cross-reference investigation with different scienti1047297c

browsers when doing bibliographical hunting As for salts implying

amino acids H-bonding interactions have been classi1047297ed in MC SC

and MCSC categories for several examples of amino acid cocrystals

For glycine and alanine only MC interactions are present in thestructures due to the lack of potential H-bond donor or acceptor

moieties on the lateral chain (Fig 10)

Several cocrystals with nucleophilic and small amino acids

(Table 2) have also been retrieved from our combined search under

their zwitterionic form with GRAS-like neutral coformers (eg

pyridine derivative (SITCUU)) (Table 2) It seems quite logical for us

to obtain zwitterionic cocrystal structures with nucleophilic or

small amino acids as they do not possess side chains likely to be

charged at physiological pH even if the counter coformer could be

(de)protonated For H-bond classi1047297cation MC and MCSC in-

teractions are present in the L -Ser cocrystal (SITCUU) but only MC

interactions exist for L -Cys cocrystal (LAWKIE) (Fig 11)

Hydrophobic amino acids (Table 3) form more zwitterionic

cocrystal structures than small or nucleophilic amino acids also

with GRAS-like compounds fumaric acid or succinic acid (VIKLUX

or EWOZIZ respectively) norvaline (BERNER or FITJEX) norleucine

(GOLVOS) or hemisuccinic acid (LABZUJ) Cocrystal structures with

other amino acids are also to be taken into account in our re-

searches combinations with other amino acids also under zwit-

terionic form even if these structures appear to be on the

boundaries of cocrystal de1047297nition deserve attention For hydro-phobic amino acids only MC H-bond interactions are present

which seems evident in view of the correspondent lateral chains

(Fig 12)

Several structures of zwitterionic cocrystals implying phenyl-

alanine with another coformer which can be an amino acid or a

GRAS-like counterpart are found in CSD and SciFinder hits Some of

these are overlapped in the two searches (with aminobutyric acid

or fumaric acid (POVYEF or VIKLOR) (Table 4)) For L -Phe and S-

mandelic acid cocrystal (NONZOF Fig13) only MC interactions are

present again with the lateral chain But surprisingly tyrosine and

tryptophan search results do not provide any hits Numerous de-

rivatives of these molecules are found alone or in certain cases in

combination with another coformer to form a salt but (zwitter-

ionic) cocrystals including these twoamino acids seem until now tobe absent from CSD and SciFinder databases Even if tyrosine could

be deprotonated tryptophan does not possess any ionizable side

chain Therefore it seems to us that this lack of cocrystal structures

for these two amino acids is surprising and deserves attention

Only one crystal structure of cocrystal for each acidic amino acid

has been retrieved with another aspartic acid molecule in a

different protonation state (HUMLIK) for aspartic acid and with

pyroglutamic acid (LGPYRG) for glutamic acid (Table 5) Presence of

the carboxylic side chain obviously favors salt formation with

ionizable counterparts for this category (see Section 22) MC SC

and MCSC interactions are all present for L -Asp cocrystal (HUMLIK)

but this structure could be considered as a special case in cocrystal

classi1047297cation In fact it could be categorized as a cocrystal of a salt

implying the amino acid in two different protonation states and the

Fig 12 Selected CSD cocrystal structures implying hydrophobic amino acids Val Leu and Pro (MC interactions for selected amino acid highlighted in black)




ionic counterpart nitrate ions On the contrary only MC in-

teractions are present in the L -Glu cocrystal (LGPYRG) (Fig 14)

One structure of asparagine and tartric acid (SUYWEP entry)

(Table 6) could be found for searches on amide amino acids MC SC

and MCSC interactions are all present on this cocrystal structure

(Fig 15) Once again even if it could be considered more as a

coincidence than a deliberate lack of use asparagine or glutamine

do not possess any controversial side chain at all permitting them

to be under zwitterionic state and to form cocrystals

In the case of basic amino acid group (His Lys and Arg) not a

single cocrystal structure could be found with CSD and SciFinder

searches even if several salts are classi1047297ed under ldquococrystalrdquo de1047297-

nition In this case it is clearly evident that the protonable basic

side chain essentially promotes salt formation

4 A case study on a particular amino acid proline

Proline appears to us as an excellent candidate to play the role of

cocrystal former It shares the zwitterionic a-ammonium-carbox-

ylate synthon common to all other natural amino acids favoring theMC interactions (enthalpic contribution) In contrast to most other

amino acids proline is a constrained rather rigid compound

Indeed the 5-membered ring ldquolateral chainrdquo is atypical among

amino acids In terms of formation of (pharmaceutical) cocrystals

this rigidity can certainly be viewed as an entropic advantage over

other more 1047298exible coformers (entropic contribution) The high

water solubility of proline (Fig1) is an extra assess for this cocrystal

former

Therefore proline has been selected as a case study for zwit-

terionic cocrystallization with therapeutic molecules First dry-

grinding reaction (a method more and more employed in cocrys-

tal formation and screening [154]) of metal salt MnCl2$4H2O with

enantiomeric L - (or D-)proline or with racemic DL -proline results in

the formation two different types of coordination complex of for-mulas [Mn(m-Cl)2(m-L -proline-k 2OO0)]1N

$H2O (nomenclature from

Ref [135b]) and [Mn(DL -proline)2(H2O)2Cl2] respectively The 1047297rst

coordination complex implies Mn (II) as metallic center and zwit-

terionic L -Pro and chloride ions as ligands L -Proin thiscase actsas a

bidentate ligand and the whole complex consists of chains of

metallic center indirectly linked by these latters This compound

has been carefully studied by X-ray diffraction and calorimetric

study to highlight the modi1047297cation of physico-chemical property

in this case the melting point [135a] With racemic proline a

resulting cluster metallic complex has been published in CSD

[135b] while the same result was highlighted during our case study

(Fig 16)

After that a classical salt former has been used to try to coc-

rystallize proline and due to zwitterionic state of this latter alreadydemonstrated in the 1047297rst formed metallic complex zwitterionic

cocrystals are obtained with the help of dry grinding [69] They

imply fumaric acid on his fully-protonated form and L -Pro D-pro or

DL -Pro all structures in a stoichiometric ratio of 21 in Pro

The last step of the study implies the use of naproxen a NSAID

member of profen family to cocrystallize with zwitterionic proline

[70] (Liquid-Assisted Grinding or LAG used in this case) In this

specimen Pro forms ldquocolumnsrdquo organizing the structures and on

which the other coformer is linked by charge-assisted hydrogen

bond Fig16 illustrates the molecular pattern of these compounds

all including zwitterionic proline

The cocrystal formation offers the same advantages to enhance

water solubility For compounds which do not possess the salt

opportunity cocrystallization with a zwitterionic compound like

Table 4

Aromatic amino acids used as zwitterionic coformers in cocrystals and their relative

crystalline structures if available

Amino

acid


Phe DL -PheSalicylic

acid [150]

L -PheD-2-aminobutyric

acid [14]L -PheD-norvaline [14]

L -PheD-Met [14]

L -PheD-Leu [14]

L -PheD-isoleucine [14]

L -PheD-allo-Ile [14]

DL -Phefumaric

acid [113]

L -PheL -Phe tetra1047298uoroboratea [137]

L -Phe7-methylguanosine-50-monophosphate

hexahydrateb [138]

D-PheR-mandelic acidc

[139]L -PhePyranetriol derivatived [140]

L -PheL -Phe sulfatee [141]

L -Phebenzoic acidf [142]

L -PheL -Phe formateg [143]

L -PheS-mandelic acidh [144]

D-PheS-mandelic acidi [144]

L -Phefumaric acid j [145]

L -PheD-2-aminobutyric acidk [14]

L -PheD-norvalinel [14]

L -PheL -phenylalanine malonatem [146]

DL -Phefumaric acidn [113]

L -Phe4-nitrophenolo [147]

DL -PheDL -Phe picratep [148]

L -Phe35-bis(tri1047298uoromethyl)phenylboronic

acid 18-crown-6q [149]

Tyr

Trp

a CADLUQb DUMJEA10c IREKARd IWIXUI01(2-(4-chloro-3-(4-ethylbenzyl)phenyl)-6-(hydroxymethyl)tetrahy-

dro-2H -pyran-345-triol monohydrate)e IZAQUVf JAXZIS

g JOTKIMh NONZOFi NONZUL j OJEPEYk POVYEFl POVYIJ

m RALRUSn VIKLORo XETLISp

YAMVISq YIWKOE

Fig 13 Selected cocrystal structure implying aromatic amino acid phenylalanine (MC

interactions for selected amino acid highlighted in black)

Table 5

Acidic amino acids used as zwitterionic coformers in cocrystals and their relative


Amino

acid

SciFinder

results

CSD structures

Asp L -AspL -Asp nitrate (HUMLIK [151])

Glu L -GluL -pyroglutamic acid

monohydrate (LGPYRG [152])




amino acids is proven to offer a suitable choice Patents of cocrystal

compounds including celecoxib [156] C-glycoside derivatives [157]

or SGLT inhibitors [158] and L -proline (Scheme 5) have been 1047297lled

recently For celecoxib cocrystallization improves oral absorption

rate due to the higher water solubility For C-glycoside derivatives

and SGLT inhibitors formation of zwitterionic cocrystals with L -

proline improves the water solubility but also the storage stability

by decreasing moisture absorptionL -Proline is also used in combination with Lithorn cations to form

ionic cocrystals (cocrystal of a salt or a metallic coordination com-

plex with an organic molecule) with particular networks These

cocrystals are claimed to lower the oral dose required to achieve

therapeutic concentrations of lithium in the brain in comparison

with conventional lithium forms [136159160]

These recent industrial examples underline once more the

importance of considering and using amino acids as promising

zwitterionic coformers for improvement of physico-chemical and

biopharmaceutical properties of newly developed compounds but

also to boost a well-known therapeutic principle exhibiting prac-

tical application issues

5 Conclusions

Using ionic counterparts with sali1047297able therapeutic compounds

is a well-known industrial and academic process in order to

Fig14 Selected cocrystal structures implying acidic amino acids aspartic acid or glutamic acid (MC SC and MCSC interactions for selected amino acid highlighted in black gray and

black dotted respectively)

Table 6

Amide amino acids used as zwitterionic coformers in cocrystals and their relative


Ami no ac id Sci Fin der r esults C SD str uctur es

Asn L -AsnL -tartric acid (SUYWEP [153])

Gln

Fig 15 Cocrystal structure implying amide amino acid asparagine (MC SC and MCSC

interactions for selected amino acid highlighted in black gray and black dotted

respectively)

Fig 16 Cocrystal structures including zwitterionic proline coming from our case study (ORTEP diagrams 50 probability [155]) a) L -Pro and MnCl2 [135a] b) DL -pro and MnCl2

(coming from personal results on top and from Ref [135b] on bottom c) L -Pro and fumaric acid (21) [69] and d) L -pro and naproxen (Columns of L -Pro on which naproxen is linked

by charge-assisted hydrogen bond) [70]




improve physico-chemical properties with in sight water

solubility

Amino acids are potentially ideal salt formers due to their

ionizable properties and their quite high water solubility (Fig 1)

They (or their derivatives) are already used in pharmaceutical ap-

plications Examples of ancient or more recent amino acid salts in

literature have been retrieved and those examples imply in many

cases therapeutic agents which have been saved from being erased

from development processes due to their inappropriate physico-

chemical properties or their poor water solubility In this review

a series of salts are presented and are thoroughly analyzed Adetailed structural outlook permits us to de1047297ne distinct patterns of

organization in main-chain and side-chain H-bonding interactions

networks Those H-bonds are charge-assisted a quite obvious

observation but that reinforces strengthening of the crystal lattice

with this class of salt formers

An extensive overlook with the help of specialized browsers

such as SciFinder or ConQuest for crystallographic entries con1047297rms

our 1047297rst guess about amino acids and their use in solid-state

pharmaceutical studies Ionizable side-chain amino acids are

more employed as salt formers and are hardly found when

searching for cocrystals including these amino acids under zwit-

terionic form But other small nucleophilic or hydrophobic amino

acids form a series of zwitterionic cocrystals These latter are for us

of primordial importance as potential zwitterionic coformer with

hypothetic non-sali1047297able API Their use has to be more and more

spread in every screening test for cocrystallizing agent selection to

resolve inappropriate physico-chemical problems as their physico-

chemical properties water solubility access ease and low cost are

enormous advantages in the industrial pharmaceutical 1047297eld

We close our investigation with a case study of L -proline as

zwitterionic cocrystal former Cocrystals with three coformers

MnCl2 fumaric acid and naproxen were obtained by grinding (neat-

grinding and LAG) They form in each case a zwitterionic structure

including L -Prolinium Recent patent examples of L -proline coc-

rystals with therapeutic compounds prove the great interest of

using amino acids as zwitterionic cocrystal formers

Acknowledgments

Authors thank Dr Luc Queacutereacute from UCB Pharma sa for fruitful

discussions and suggestions and his support during all the work

AT thanks the ldquo Fonds pour la formation agrave la Recherche dans

lrsquoIndustrie et dans lrsquoAgriculturerdquo (FRIA ) for its grant and support

Financial support of the FNRS grant n 2451107 is also

acknowledged

References

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[2] AV Trask WDS Motherwell W Jones Physical stability enhancement of theophylline via cocrystallization Int J Pharm 320 (2007) 114e123

[3] Y Qiu Y Chen GZ Zhang L Liu W Porter Developing Solid Oral Dosage

Forms Elsevier NY USA 2009

[4] R Hil1047297ker (Ed) Polymorphism in the Pharmaceutical Industry Wiley-VCHGermany 2006

[5] J Wouters L Queacutereacute (Eds) Pharmaceuticals Salts and Cocrystals RSC Pub-lishing Oxford UK 2012

[6] (a) AL Weber SL Miller Reasons for the occurrence of the twenty codedprotein amino acids J Mol Evol 17 (5) (1981) 273e284(b) J Kyte RF Doolittle A simple method for displaying the hydropathiccharacter of a protein J Mol Biol 157 (1982) 105e132(c) RF Doolittle Redundancies in protein sequence in GD Fasman (Ed)Prediction of Protein Structures and the Principles of Protein ConformationPlenum Press NY 1989 pp 599e623(d) JP Hamend HC Helgeson Solubilities of the common L -a-amino acids asa function of temperature and solution pH Pure Appl Chem 69 (1997) 935e942

[7] DJ Ager DP Pantaleone SA Henderson AR Katritzky I PrakashDE Walters Commercial synthetic non-nutritive sweeteners Angew ChemInt Ed 37 (13e24) (1998) 1802e1817

[8] Pallas 3712 CompuDrug Chemistry Ltd Copyright CompuDrug 1994e2006

[9] L Borgstroumlm B Karinggedal O Paulsen Pharmacokinetics of N -acetylcysteine inman Eur J Clin Pharm 31 (2) (1986) 217e222

[10] FW Flitney RJ Pritchard GD Kennovin SK Bisland DG Hirst SP FrickerAntitumor actions of ruthenium(III)-based nitric oxide scavengers and nitricoxide synthase inhibitors Mol Cancer Ther 10 (9) (2011) 1571e1580

[11] B Dalhus CH Goumlrbitz Molecular aggregation in crystalline 11 complexes of hydrophobic D- and L -amino acids I The L -isoleucine series Acta CrystallogrSect B Struct Crystallogr Cryst Chem 55 (1999) 424e431

[12] B Dalhus CH Goumlrbitz Molecular aggregation in selected crystalline 11complexes of hydrophobic D - and L -amino acids II The D -norleucine seriesActa Crystallogr Sect C Cryst Struct Commun 55 (1999) 1105e1112

[13] B Dalhus CH Goumlrbitz Molecular aggregation in selected crystalline 11complexes of hydrophobic D- and L -amino acids III The L -leucine and L -

valine series Acta Crystallogr Sect C Cryst Struct Commun 55 (1999)1547e1555[14] CH Goumlrbitz K Rissanen A Valkonen A Husaboslash Molecular aggregation in

selected crystalline 11 complexes of hydrophobic D - and L -amino acids IVThe L -phenylalanine series Acta Crystallogr Sect C Cryst Struct Commun65 (2009) o267eo272

[15] G Bastiat JC Leroux Pharmaceutical organogels prepared from aromaticamino acid derivatives J Mater Chem 19 (2009) 3867e3877

[16] B Kozier G Erb AJ Herman K Burke SR Bouchal SP Hirst Fundamentalsof Nursing The Nature of Nursing Practice in Canada Canadian ed PrenticeHall Health Toronto Canada 2004

[17] REC Wildman (Ed) Handbook of Nutraceuticals and Functional Foods 1047297rsted CRC Press Series (Modern Nutrition) Boca Raton Florida USA 2001

[18] FH Allen The Cambridge Structural Database a quarter million structuresand rising Acta Crystallogr Sect B Struct Crystallogr Cryst Chem 58 (2002)380e388

[19] SciFinder CAS (Chemical Abstracts Service) Web-based Interface fromAmerican Chemical Society (ACS) Copyright American Chemical Society2013

[20] Physico-chemical Tables for pKa CRC Handbook (2010 version) Boca RatonFlorida USA

[21] DM Salunke M Vijayan X-ray studies on crystalline complexes involvingamino acids and peptides IX Crystal structure of L -ornithine L -aspartatehemihydrate Int J Pept Protein Res 22 (1983) 154

[22] T Yamada X Liu U Englert H Yamane R Dronskowski Solid-state struc-ture of free base guanidine achieved at last Chem Eur J 15 (23) (2009)5651e5655

[23] W Krumbe S Haussuhl Structure and physical properties of orthorhombicguanidinium phthalate [CN3H6]2C8H4O4 and guanidinium hydrogen L -aspartate [CN3H6]C4H6NO4 Z Kristallogr 179 (1987) 267e280

[24] TH Jukes Some historical notes on chlortetracycline Rev Infect Dis 7 (5)(1985) 702e707

[25] S Inouye Y Iitaka Crystallographic data on the molecular complexes of tetracycline salts Acta Crystallogr 17 (1964) 207e208

[26] B Peng Q Peng W Zhou Z Zhou Guanidinium L -glutamate Acta Crys-tallogr Sect E Struct Rep Online 66 (2010) o2679

[27] JW Steed JL Atwood Supramolecular Chemistry second ed Wiley-VCHGermany 2009

Scheme 5 Structures of celecoxib C-glycoside derivatives and SGLT inhibitors patented with proline to form cocrystals enhancing water solubility or storage stability of the

compound [156e158]




[28] AN Chekhlov 110-Diazonia-18-crown-6 bis(DL -glutamate) Russ J GenChem 71 (2001) 119

[29] A Albert (Ed) Heterocyclic Chemistry second ed Athlone Press LondonUK 1968

[30] CH Goumlrbitz J Husdal Cocrystallizing agents for amino acids I The crystalstructure of L -glutamic acid 2-Methylimidazole Acta Chem Scand 50 (1996)796e801

[31] S Bhattacharya AK Bera S Ghosh S Chakraborty BP MukhopadhyayA Pal A Banerjee Regiospeci1047297city of nucleotideeamino acid mating vswater dynamics a key to proteinenucleic acid assemblies structure of

unidecahydrated inosine-50-monophosphate and L -glutamic acid cocrystal atatomic resolution J Chem Cryst 30 (2000) 655e663

[32] W Haglund Forensic Taphonomy The Postmortem Fate of Human RemainsCRC Press Series Boca Raton Florida USA 1996

[33] S Ramaswamy M Nethaji MRN Murthy Crystal structure of putrescine e

glutamic acid complex Curr Sci 58 (1989) 1160e1162[34] S Ramaswamy MRN Murthy The crystal and molecular structure of pu-

trescineedi-glutamic acid complexes Curr Sci 61 (1991) 410e412[35] CG Suresh J Ramaswamy M Vijayan X-ray studies of crystalline com-

plexes involving amino acids and peptides XIII Effect of chirality on mo-lecular aggregation the crystal structures of L -arginine D-aspartate and L -arginine D -glutamate trihydrate Acta Crystallogr Sect B Struct CrystallogrCryst Chem 42 (1986) 473e478

[36] J Soman M Vijayan B Ramakrishnan TNG Row X-ray studies on crys-talline complexes involving amino acids and peptides XVII Chirality andmolecular aggregation the crystal structures of DL -arginine DL -glutamatemonohydrate and DL -arginine DL -aspartate Biopolymers 29 (1990) 533e542

[37] DM Salunke M Vijayan L -Arginine L -aspartate Acta Crystallogr Sect BStruct Crystallogr Cryst Chem 38 (1982) 1328e1330

[38] J Soman CG Suresh M Vijayan X-ray studies on crystalline complexesinvolving amino acids and peptides XV Crystal structures of L -lysine D-glutamate and L -lysine D-asparate monohydrate and the effect of chirality onmolecular aggregation Int J Pept Protein Res 32 (1988) 352e360

[39] TN Bhat M Vijayan X-ray studies of crystalline complexes involving aminoacids II The crystal structure of L -arginine L -glutamate Acta Crystallogr SectB Struct Crystallogr Cryst Chem 33 (1977) 1754e1759

[40] J Soman M Vijayan X-ray studies on crystalline complexes involving aminoacids and peptides part XVIII Crystal structure of a new form of L -arginine D-glutamate anda comparativestudy of aminoacid crystal structurescontainingmolecules of the same and mixed chirality J Biosci 14 (1989) 111e125

[41] V Bertolasi P Gilli V Ferretti G Gilli Resonance-assisted 0-H 0 hydrogenbonding its role in the crystalline self-recognition of B-diketone enols and itsstructural and IR characterization Chem Eur J 2 (8) (1996) 925e934

[42] GR Desiraju T Steiner The Weak Hydrogen Bond in Structural Chemistryand Biology in International Union of Crystallography (IUCr) Monographson Crystallography vol 9 Oxford University Press Inc New York USA 1999

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Org Synth Coll 2 (1943) 531(b) A Muumlller Pimelic acid from salicylic acid Org Synth Coll 11 (1931) 42 [44] D Voet JG Voet CW Pratt Fundamentals of Biochemistry Life at the

Molecular Level second ed Wiley amp Sons Hoboken New Jersey USA 2006 [45] NT Saraswathi S Roy M Vijayan X-ray studies on crystalline complexes

involving amino acids and peptides XLI Commonalities in aggregation andconformation revealed by the crystal structures of the pimelic acid com-plexes of L -arginine and DL -lysine Acta Crystallogr Sect B Struct CrystallogrCryst Chem 59 (2003) 641e646

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[47] GI Brown (Ed) The Big Bang a History of Explosives Sutton PublishingStroud UK 1998

[48] CD Gutsche Calixarenes Revisited RSC Publishing Cambridge UK 1998 [49] FL Carson C Hladik Histotechnology a Self-instructional Text third ed

American Society for Clinical Pathology Press USA 2009 [50] H Nagata Y In K Tomoo M Doi T Ishida A Wakahara Structural feature

and molecular interaction of basic amino acidepicric acid complexes by X-

ray crystal analyses Chem Pharm Bull 43 (1995) 1836e

1843[51] M Selkti AW Coleman I Nicolis N Douteau-Guevel F Villain A Tomas

C de Rango The 1047297rst example of a substrate spanning the calix[4]arenebilayer the solid state complex of P-sulfonatocalix[4]arene with L -lysineChem Commun (2000) 161e162

[52] WH Ojala EA Sudbeck LK Lu TI Richardson RE Lovrien WB GleasonComplexes of lysine histidine and arginine with sulfonated azo dyesmodel systems for understanding the biomolecular recognition of glycos-aminoglycans by proteins J Am Chem Soc 118 (1996) 2131e2142

[53] Merck Index tenth ed 1983 ISBN 0-911910-27-1 [54] A Avdeef DA Barrett PN Shaw RD Knaggs SS Davis Octanole chlo-

roforme and propylene glycol dipelargonatewater partitioning of morphine-6-glucuronide and other related opiates J Med Chem 39 (22)(1996) 4377e4381

[55] J Sangster OctanoleWater Partition Coef 1047297cients Fundamentals and PhysicalChemistry Wiley amp Sons New York USA 1994

[56] ME Falagas AP Grammatikos A Michalopoulos Potential of old-generation antibiotics to address current need for new antibiotics ExpertRev Anti-Infect Ther 6 (5) (2008) 593e600

[57] L Zhao CH Ball Determination of Chloramphenicol Florfenicol andThiamphenicol in Honey Using Agilent SampliQ OPT Solid-phase ExtractionCartridges and Liquid Chromatography-tandem Mass Spectrometry Appli-cation Notes in Food Safety Agilent Technologies 2009

[58] Merck Index twelfth ed 1996 ISBN 0-911910-12-3 [59] LP Garrod Relative antibacterial activity of three penicillins Br Med J 1

(5172) (1960) 527e529[60] G Kortuumlm W Vogel K Andrussar Pure Appl Chem 1 (1961) 187e188[61] PF Schellhammer An evaluation of bicalutamide in the treatment of pros-

tate cancer Expert Opin Pharmacother 3 (9) (2002) 1313e1328

[62] DC Hooper Quinolone Antimicrobial Agents third ed ASM Press USA2003

[63] W Sneader The discovery of aspirin a reappraisal BMJ e Clin Res 321(7276) (2000) 1591e1594

[64] JP Bounhoure G Bottineau P Lechat Value of perindopril in the treatmentof chronic congestive heart failure multicentre double-blind placebo-controlled study Clin Exp Hypertens A11 (Suppl 2) (1989) 575e586

[65] BK Skrumsager KK Nielsen M Muumlller G Pabst PG Drake B EdsbergRagaglitazar the pharmacokinetics pharmacodynamics and tolerability of anovel dual PPAR alpha and gamma agonist in healthy subjects and patientswith type 2 diabetes J Clin Pharmacol 43 (11) (2003) 1244 e1256

[66] S EbdrupI Pettersson HBRasmussenHJ DeussenAFJensen SBMortensen J Fleckner L Pridal L Nygaard P Sauerberg Synthesis and biological andstructural characterization of the dual-acting peroxisomeproliferator-activatedreceptor ag agonist ragaglitazar J Med Chem 46 (2003) 1306e1317

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[111] S Pandiarajan B Sridhar RK Rajaram L -Valine L -valinium perchloratemonohydrate Acta Crystallogr Sect E Struct Rep Online 57 (2001) o466

[112] GS Prasad M Vijayan X-ray studies on crystalline complexes involvingamino acids and peptides XXI Structure of a (11) complex between L -phenylalanine and D-valine Acta Crystallogr Sect C Cryst Struct Commun47 (1991) 2603e2606

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[116] B Dalhus CH Goumlrbitz Structural relationships in crystals accommodatingdifferent stereoisomers of 2-amino-3-methylpentanoic acid Acta Crys-tallogr Sect B Struct Crystallogr Cryst Chem 56 (2000) 720e727

[117] Jian-Rong Su Duan-Jun Xu (R)-Methioninium(R)-mandelate (R)-mandelate(R)-mandelic acid Acta Crystallogr Sect E Struct Rep Online 61 (2005)o1933

[118] B Sridhar N Srinivasan B Dalhus RK Rajaram L -Methionine L -methioni-nium perchlorate monohydrate Acta Crystallogr Sect E Struct Rep Online58 (2002) o779

[119] K Anitha S Athimoolam RK Rajaram DL -Methionine DL -methioniniumpicrate Acta Crystallogr Sect E Struct Rep Online 62 (2006) o8

[120] GS Prasad M Vijayan X-ray studies on crystalline complexes involvingamino acids and peptides XXV Structures of DL -proline hemisuccinic acidand glycyl-L -histidinium semisuccinate monohydrate and a comparativestudy of amino-acid and peptide complexes of succinic acid Acta CrystallogrSect B Struct Crystallogr Cryst Chem 49 (1993) 348e349

[121] VV Gharzaryan M Fleck P Petrosyan L -ProliniumL -proline tetra-1047298uoroborate Proc SPIE 7998 (2011) 79980

[122] S Athimoolam S Natarajan Hydrogen-bonding features in the 12 adduct of 4-aminobenzoic acid and L -proline Acta Crystallogr Sect C Cryst StructCommun 63 (2007) o283eo286

[123] S Muramulla HD Arman CG Zhao ERT Tiekink L -Prolinium meth-anolate(S RRRS S )-1-[35-bis(tri1047298uoromethyl)phenyl]-3-[(5-ethenyl-1-azabicyclo[222]octan-2-yl)(6-methoxyquinolin-4-yl)methyl]thiourea ActaCrystallogr Sect E Struct Rep Online 65 (2009) o3070

[124] CR Ramanathan M Periasamy Resolution of C2-symmetric 910-dihydro-910-ethanoanthracene-1112-dicarboxylic acid and 23-diphenylsuccinicacid using (S )-proline Tetrahedron Asymmetry 9 (1998) 2651e2656

[125] S Pandiarajan B Sridhar RK Rajaram L -proliniumL -proline perchlorateActa Crystallogr Sect E Struct Rep Online 58 (2002) o74eo76

[126] TV Timofeeva GH Kuhn VV Nesterov VN Nesterov DO FrazierBG Penn MY Antipin Cocrystal of 11-dicyano-2-(4-hydroxyphenyl)-ethene with l-proline and induced conformational polymorphism of 11-dicyano-2-(4-hydroxy- 3-methoxyphenyl)-ethene Cryst Growth Des 3(2003) 383e391

[127] P Rogowska MK Cyranski A Sporzynski A Ciesielski Evidence for strongheterodimeric interactions of phenylboronic acids with amino acids Tetra-hedron Lett 47 (2006) 1389e1393

[128] S Pandiarajan B Sridhar RK Rajaram L -Prolinium L -proline nitrate ActaCrystallogr Sect E Struct Rep Online 58 (2002) o1370eo1371

[129] X Qu J Lu C Zhao JF Boas B Moubaraki KS Murray A SiriwardanaAM Bond LL Martin An amino acid derived semiconductor Angew ChemInt Ed 50 (7) (2011) 1589e1592

[130] TY Fu JR Scheffer J Trotter Phenyl[246-tris(1 methylethyl)phenyl]methanethione and 4-methoxyphenyl[246-tris(1-methylethyl)phenyl]methanethione Acta Crystallogr Sect C Cryst Struct Commun 53 (1997)1257e1259

[131] GA Jeffrey An Introduction to Hydrogen Bonding Oxford University PressNew York USA 1997

[132] CB Aakeroy GS Bahra CR Brown PB Hitchcock Y Patell KR Seddon L -Proline 25-dihydroxybenzoic acid (11) a zwitterion co-crystal Acta ChemScand 49 (1995) 762e767

[133] PP Deshpande J Singh A Pullockaran T Kissick BA Ellsworth

JZ Gougo utas J Dimarco M Fakes M Reyes C Lai H Lobinger T DenzelP Ermann G Crispino M Randazzo Z Gao R Randazzo M LindrudV Rosso F Buono WW Doubleday S Leung P Richberg D HughesWN Washburn W Meng KJ Volk RH Mueller A practical stereoselectivesynthesis and novel cocrystallizations of an amphiphatic SGLT-2 inhibitorOrg Process Res Dev 16 (2012) 577e585

[134] A Alhalaweh S George S Basavoju SL Childs SAA Rizvic SP VelagaPharmaceutical cocrystals of nitrofurantoin screening characterization andcrystal structure analysis CrystEngComm 14 (2012) 5078e5088

[135] (a) A Tilborg C Michaux B Norberg J Wouters Advantages of cocrystal-lization in the 1047297eld of solid-state pharmaceutical chemistry L -proline andMnCl2 Eur J Med Chem 45 (2010) 3511e3517(b) K Lamberts U Englert Structures from MnX2 and proline isomorphousracemic compounds and a series of chiral non-isomorphous chain polymersActa Crystallogr Sect B Struct Crystallogr Cryst Chem 68 (2012) 610e618

[136] TT Ong P Kavuru T Nguyen R Cantwell Y Wojtas MJ Zaworotko 21Cocrystals of homochiral and achiral amino acid zwitterions with Li saltswaterestable zeolitic and diamondoid metal organic materials J Am ChemSoc 133 (2011) 9224e9227

[137] VV Gharzaryan M Fleck AM Petrosyan L -Phenylalaninium L -phenylala-nine tetra1047298uoroborate Proc SPIE 7998 (2011) 79980F

[138] T Ishida M Doi M Inoue L -Phenylalanine 7-methylguanosine-50-mono-phosphate hexahydrate Nucleic Acids Res 16 (1988) 6175

[139] Zi-Qiang Hu Duan-Jun Xu Yuan-Zhi Xu Jing-Yun Wu MY Chiang (R)-Phenylalanine (R)-mandelic acid Chin J Struct Chem 23 (2004) 38

[140] PP Deshpande LL Shen JZ Gougoutas l-Phenylalanine 2-(4-chloro-3-(4-ethylbenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H -pyran-345-triolmonohydrate US Patents (2008) USA

[141] Yu-Xi Sun Zhong-Lu You 2-Ammonio-3-phenylpropanoic acid 2-ammonio-3-phenylpropanoate sulfate Acta Crystallogr E60 (2004) o1447

[142] J Suresh RV Krishnakumar S Natarajan L -Phenylalanine benzoic acidsolvate Acta Crystallogr Sect E Struct Rep Online 61 (2005) o3625

[143] CH Goumlrbitz MC Etter Structure of L -phenylalanine L -phenylalaniniumformate Acta Crystallogr Sect C Cryst Struct Commun 48 (1992) 1317e1320

[144] K Okamura K Aoe H Hiramatsu N Nishimura T Sato K HashimotoCrystal structures of diastereomeric 11 complexes of (R)-and (S )-phenylal-anine (S )-mandelic acid Anal Sci 13 (1997) 315e318




[145] M Alagar RV Krishnakumar K Rajagopal MS Nandhini S Natarajan L -Phenylalanine fumaric acid Acta Crystallogr Sect E Struct Rep Online 59(2003) o952

[146] M Alagar RV Krishnakumar PP Devi S Natarajan L -Phenylalanine L -phenylalaninium malonate Acta Crystallogr Sect E Struct Rep Online 61(2005) o992

[147] VH Rodrigues MMRR Costa E de M Gomes E Nogueira M Belslsey L -Phenylalanine-4-nitrophenol (11) Acta Crystallogr Sect C Cryst StructCommun 62 (2006) o699eo701

[148] K Anitha RK Rajaram DL -Phenylalanine DL -phenylalaninium picrate Acta

Crystallogr Sect E Struct Rep Online 61 (2005) o589 [149] MT Reetz J Huff J Rudolph K Tollner A Deege R Goddard Highly ef 1047297-

cient transport of amino acids through liquid membranes via three-component supramolecules J Am Chem Soc 116 (1994) 11588e11589

[150] MA Elbagerma HGM Edwards T Munshi MD HargreavesPavel Matousek IJ Scowen Characterization of new cocrystals by Ramanspectroscopy powder X-ray diffraction Differential scanning calorimetryand transmission raman spectroscopy Cryst Growth Des 10 (2010) 2360e

2371[151] B Sridhar N Srinivasan RK Rajaram Bis(L -aspartatic acid) nitrate Acta

Crystallogr Sect E Struct Rep Online 58 (2002) o1372 [152] Z Taira WH Watson The structure of a 11 mixed crystal of L -glutamic acid

and L -pyroglutamic acid and a re1047297nement of the structure of pyroglutamic

acid Acta Crystallogr Sect B Struct Crystallogr Cryst Chem 33 (1977)3823e3827

[153] S Natarajan V Hema JK Sundar J Suresh PLN Lakshman 4-Amino-2-ammonio-4-oxobutanoate 23-dihydroxysuccinate Acta Crystallogr Sect EStruct Rep Online 66 (2010) o2239

[154] T Fris

c

ic

W Jones Recent advances in understanding the mechanism of cocrystal formation via grinding Cryst Growth Des 9 (3) (2009) 1621e1637

[155] MN Burnett CK Johnson ORTEP-III Oak Ridge Thermal Ellipsoid PlotProgram for Crystal Structure Illustrations Oak Ridge National LaboratoryUSA 1996 Report ORNL-6895

[156] CR Plata Salaman N Tesson Co-crystals of Celecoxib and L -proline Euro-pean Patent EP 2325172 2011 Barcelona Muumlnchen ES DE

[157] M Imamura K Nakanishi R Shiraki K Onda D Sasuga M Yuda Cocrystalof C-glycoside derivative and L -proline US 20090143316 A 2007 TokyoNagano JP

[158] BM Collman V Mascitti Dioxa-bicyclo[321]octane-234-triol derivativesUS 8080580 B2 2009 CT USA

[159] MJ Zaworotko RD Shytle TT Ong P Kavuru RL Cantwell T Nguyen AJSmith Lithium compositions US2012030586 2012 FL USA

[160] RD Shytle AJ Smith P Kavuru MJ Zaworotko A novel lithium cocrystalwith improved oral bioavailability and targeted brain delivery Cell Trans-plant 21 (4) (2012) 792e797




application that a careful decision implicating all facets of the

problem is mandatory for the proper salt development process

In this context amino acids (Fig 1 [6abcd]) seem to be a

valuable choice as suitable salt partners They are GRAS com-

pounds with a very low toxicity easily reachable in terms of

implementation in the process and non-expensive They are

already implicated in a variety of developed and marketed phar-

maceutical salts A brief overview of the place of amino acids in

chemical and pharmaceutical sciences follows in the next section

2 Amino acids

21 Overview of amino acids in chemical and pharmaceutical

sciences

Before being suitable salt counterions for pharmaceutical

agents amino acids (Fig 1) and their derivatives can be found in

a variety of therapeutic compounds but also in daily-life

products

The most common example to be cited is phenylalanine and

aspartic acid which are the two constituents of aspartame [7]

(Scheme 1 pKa frac14 325 (acidic group) pKa frac14 812 (basic group)

predicted values from Pallas [8]) For derivatives a well-known

case is acetylcysteine [9] e directly derived from cysteine e used

as an antidote in case of acetaminophen overdose and as anti-

obsessive compulsive disorder drug (pKa frac14 325 (acidic group)

pKa frac14 1074 (basic group) predicted values from Pallas [8]) N6-

Cbz-L -lysine benzyl ester hydrochloride a derivative of lysine is

used during preparation of antithrombotic agents [10] (Scheme 1)

From a more organic point of view one can cite leucine isoleucine

valine alanine phenylalanine methionine and some derivatives as

norvaline norleucine or 2-aminobutyric acid that are crystallized

together to study chiral aggregation [11e14] Alanine phenylala-

nine tyrosine and tryptophane are used as pharmaceutical

Fig1 20 natural L -amino acids developed formulas (at physiological pH) three-letter and one-letter peptic codes molecular weight (MW) isoelectric point (pI) hydropathy index

(Hydropathy) [6b] occurrence in proteins in (occurrence) [6c] and water solubility (g100 mL at 25

C solubility) [6d]





neoyl esters [15]


























state sciences







cocrystals





[15]
































































bonds) (Fig 5)







































(Scheme 2)







Pallas






values from Pallas














































respectively)



respectively)






Amino

acid



GlyNaNO3 [91]









monohydrateh [96]


acidi [97]





hemihydratem [102]



m

XUGMER















3 Cocrystals





















Table 2



Amino

acid



acid [103]


acida [103]


monohydrateb [104]









































Table 3



Amino

acid



acid [13]


D-ValL -Leua [13]



L -ValD-Metd


D-ValL -Ilef [11]


[108]





[111]

D-ValL -Phel [112]




L -LeuD-Metp [13]

D-LeuL -Ileq [11]

L -LeuL -Leur [114]


D-LeuL -Phet [14]





L -IleD-Met [11]

L -IleL -Phe [14]


L -IleD-Alav [11]




L -IleD-Metz [11]

D-IleL -Pheaa [14]



[117]


D-MetL -Pheae [14]



monohydrateag [118]





[126]

L -Pro4-


[127]



L -ProLiCl [136]



acidal [122]


derivativeam [123]








[127]


L -Probis(7788-








[132]



k QOQWEYl SONCED







ak CADKOJal CIDBOH



au VESCUSav ZEZHIV





Figs 10e15








































(Fig 12)





















































former


















(Fig 16)
















Table 4



Amino

acid



acid [150]



L -PheD-Met [14]

L -PheD-Leu [14]



DL -Phefumaric

acid [113]



hexahydrateb [138]

















Tyr

Trp





YAMVISq YIWKOE



Table 5



Amino

acid

SciFinder

results

CSD structures


























5 Conclusions





Table 6





Gln



respectively)








solubility



































Acknowledgments






acknowledged

References































compound [156e158]


































































338





















































































[154] T Fris

c

ic












neoyl esters [15]


























state sciences







cocrystals





[15]
































































bonds) (Fig 5)







































(Scheme 2)







Pallas






values from Pallas














































respectively)



respectively)






Amino

acid



GlyNaNO3 [91]









monohydrateh [96]


acidi [97]





hemihydratem [102]



m

XUGMER















3 Cocrystals





















Table 2



Amino

acid



acid [103]


acida [103]


monohydrateb [104]









































Table 3



Amino

acid



acid [13]


D-ValL -Leua [13]



L -ValD-Metd


D-ValL -Ilef [11]


[108]





[111]

D-ValL -Phel [112]




L -LeuD-Metp [13]

D-LeuL -Ileq [11]

L -LeuL -Leur [114]


D-LeuL -Phet [14]





L -IleD-Met [11]

L -IleL -Phe [14]


L -IleD-Alav [11]




L -IleD-Metz [11]

D-IleL -Pheaa [14]



[117]


D-MetL -Pheae [14]



monohydrateag [118]





[126]

L -Pro4-


[127]



L -ProLiCl [136]



acidal [122]


derivativeam [123]








[127]


L -Probis(7788-








[132]



k QOQWEYl SONCED







ak CADKOJal CIDBOH



au VESCUSav ZEZHIV





Figs 10e15








































(Fig 12)





















































former


















(Fig 16)
















Table 4



Amino

acid



acid [150]



L -PheD-Met [14]

L -PheD-Leu [14]



DL -Phefumaric

acid [113]



hexahydrateb [138]

















Tyr

Trp





YAMVISq YIWKOE



Table 5



Amino

acid

SciFinder

results

CSD structures


























5 Conclusions





Table 6





Gln



respectively)








solubility



































Acknowledgments






acknowledged

References































compound [156e158]


































































338





















































































[154] T Fris

c

ic




































































bonds) (Fig 5)







































(Scheme 2)







Pallas






values from Pallas














































respectively)



respectively)






Amino

acid



GlyNaNO3 [91]









monohydrateh [96]


acidi [97]





hemihydratem [102]



m

XUGMER















3 Cocrystals





















Table 2



Amino

acid



acid [103]


acida [103]


monohydrateb [104]









































Table 3



Amino

acid



acid [13]


D-ValL -Leua [13]



L -ValD-Metd


D-ValL -Ilef [11]


[108]





[111]

D-ValL -Phel [112]




L -LeuD-Metp [13]

D-LeuL -Ileq [11]

L -LeuL -Leur [114]


D-LeuL -Phet [14]





L -IleD-Met [11]

L -IleL -Phe [14]


L -IleD-Alav [11]




L -IleD-Metz [11]

D-IleL -Pheaa [14]



[117]


D-MetL -Pheae [14]



monohydrateag [118]





[126]

L -Pro4-


[127]



L -ProLiCl [136]



acidal [122]


derivativeam [123]








[127]


L -Probis(7788-








[132]



k QOQWEYl SONCED







ak CADKOJal CIDBOH



au VESCUSav ZEZHIV





Figs 10e15








































(Fig 12)





















































former


















(Fig 16)
















Table 4



Amino

acid



acid [150]



L -PheD-Met [14]

L -PheD-Leu [14]



DL -Phefumaric

acid [113]



hexahydrateb [138]

















Tyr

Trp





YAMVISq YIWKOE



Table 5



Amino

acid

SciFinder

results

CSD structures


























5 Conclusions





Table 6





Gln



respectively)








solubility



































Acknowledgments






acknowledged

References































compound [156e158]


































































338





















































































[154] T Fris

c

ic





















(Scheme 2)







Pallas






values from Pallas














































respectively)



respectively)






Amino

acid



GlyNaNO3 [91]









monohydrateh [96]


acidi [97]





hemihydratem [102]



m

XUGMER















3 Cocrystals





















Table 2



Amino

acid



acid [103]


acida [103]


monohydrateb [104]









































Table 3



Amino

acid



acid [13]


D-ValL -Leua [13]



L -ValD-Metd


D-ValL -Ilef [11]


[108]





[111]

D-ValL -Phel [112]




L -LeuD-Metp [13]

D-LeuL -Ileq [11]

L -LeuL -Leur [114]


D-LeuL -Phet [14]





L -IleD-Met [11]

L -IleL -Phe [14]


L -IleD-Alav [11]




L -IleD-Metz [11]

D-IleL -Pheaa [14]



[117]


D-MetL -Pheae [14]



monohydrateag [118]





[126]

L -Pro4-


[127]



L -ProLiCl [136]



acidal [122]


derivativeam [123]








[127]


L -Probis(7788-








[132]



k QOQWEYl SONCED







ak CADKOJal CIDBOH



au VESCUSav ZEZHIV





Figs 10e15








































(Fig 12)





















































former


















(Fig 16)
















Table 4



Amino

acid



acid [150]



L -PheD-Met [14]

L -PheD-Leu [14]



DL -Phefumaric

acid [113]



hexahydrateb [138]

















Tyr

Trp





YAMVISq YIWKOE



Table 5



Amino

acid

SciFinder

results

CSD structures


























5 Conclusions





Table 6





Gln



respectively)








solubility



































Acknowledgments






acknowledged

References































compound [156e158]


































































338





















































































[154] T Fris

c

ic



































respectively)



respectively)






Amino

acid



GlyNaNO3 [91]









monohydrateh [96]


acidi [97]





hemihydratem [102]



m

XUGMER















3 Cocrystals





















Table 2



Amino

acid



acid [103]


acida [103]


monohydrateb [104]









































Table 3



Amino

acid



acid [13]


D-ValL -Leua [13]



L -ValD-Metd


D-ValL -Ilef [11]


[108]





[111]

D-ValL -Phel [112]




L -LeuD-Metp [13]

D-LeuL -Ileq [11]

L -LeuL -Leur [114]


D-LeuL -Phet [14]





L -IleD-Met [11]

L -IleL -Phe [14]


L -IleD-Alav [11]




L -IleD-Metz [11]

D-IleL -Pheaa [14]



[117]


D-MetL -Pheae [14]



monohydrateag [118]





[126]

L -Pro4-


[127]



L -ProLiCl [136]



acidal [122]


derivativeam [123]








[127]


L -Probis(7788-








[132]



k QOQWEYl SONCED







ak CADKOJal CIDBOH



au VESCUSav ZEZHIV





Figs 10e15








































(Fig 12)





















































former


















(Fig 16)
















Table 4



Amino

acid



acid [150]



L -PheD-Met [14]

L -PheD-Leu [14]



DL -Phefumaric

acid [113]



hexahydrateb [138]

















Tyr

Trp





YAMVISq YIWKOE



Table 5



Amino

acid

SciFinder

results

CSD structures


























5 Conclusions





Table 6





Gln



respectively)








solubility



































Acknowledgments






acknowledged

References































compound [156e158]


































































338





















































































[154] T Fris

c

ic






















3 Cocrystals





















Table 2



Amino

acid



acid [103]


acida [103]


monohydrateb [104]









































Table 3



Amino

acid



acid [13]


D-ValL -Leua [13]



L -ValD-Metd


D-ValL -Ilef [11]


[108]





[111]

D-ValL -Phel [112]




L -LeuD-Metp [13]

D-LeuL -Ileq [11]

L -LeuL -Leur [114]


D-LeuL -Phet [14]





L -IleD-Met [11]

L -IleL -Phe [14]


L -IleD-Alav [11]




L -IleD-Metz [11]

D-IleL -Pheaa [14]



[117]


D-MetL -Pheae [14]



monohydrateag [118]





[126]

L -Pro4-


[127]



L -ProLiCl [136]



acidal [122]


derivativeam [123]








[127]


L -Probis(7788-








[132]



k QOQWEYl SONCED







ak CADKOJal CIDBOH



au VESCUSav ZEZHIV





Figs 10e15








































(Fig 12)





















































former


















(Fig 16)
















Table 4



Amino

acid



acid [150]



L -PheD-Met [14]

L -PheD-Leu [14]



DL -Phefumaric

acid [113]



hexahydrateb [138]

















Tyr

Trp





YAMVISq YIWKOE



Table 5



Amino

acid

SciFinder

results

CSD structures


























5 Conclusions





Table 6





Gln



respectively)








solubility



































Acknowledgments






acknowledged

References































compound [156e158]


































































338





















































































[154] T Fris

c

ic








































Table 3



Amino

acid



acid [13]


D-ValL -Leua [13]



L -ValD-Metd


D-ValL -Ilef [11]


[108]





[111]

D-ValL -Phel [112]




L -LeuD-Metp [13]

D-LeuL -Ileq [11]

L -LeuL -Leur [114]


D-LeuL -Phet [14]





L -IleD-Met [11]

L -IleL -Phe [14]


L -IleD-Alav [11]




L -IleD-Metz [11]

D-IleL -Pheaa [14]



[117]


D-MetL -Pheae [14]



monohydrateag [118]





[126]

L -Pro4-


[127]



L -ProLiCl [136]



acidal [122]


derivativeam [123]








[127]


L -Probis(7788-








[132]



k QOQWEYl SONCED







ak CADKOJal CIDBOH



au VESCUSav ZEZHIV





Figs 10e15








































(Fig 12)





















































former


















(Fig 16)
















Table 4



Amino

acid



acid [150]



L -PheD-Met [14]

L -PheD-Leu [14]



DL -Phefumaric

acid [113]



hexahydrateb [138]

















Tyr

Trp





YAMVISq YIWKOE



Table 5



Amino

acid

SciFinder

results

CSD structures


























5 Conclusions





Table 6





Gln



respectively)








solubility



































Acknowledgments






acknowledged

References































compound [156e158]


































































338





















































































[154] T Fris

c

ic












Figs 10e15








































(Fig 12)





















































former


















(Fig 16)
















Table 4



Amino

acid



acid [150]



L -PheD-Met [14]

L -PheD-Leu [14]



DL -Phefumaric

acid [113]



hexahydrateb [138]

















Tyr

Trp





YAMVISq YIWKOE



Table 5



Amino

acid

SciFinder

results

CSD structures


























5 Conclusions





Table 6





Gln



respectively)








solubility



































Acknowledgments






acknowledged

References































compound [156e158]


































































338





















































































[154] T Fris

c

ic



































former


















(Fig 16)
















Table 4



Amino

acid



acid [150]



L -PheD-Met [14]

L -PheD-Leu [14]



DL -Phefumaric

acid [113]



hexahydrateb [138]

















Tyr

Trp





YAMVISq YIWKOE



Table 5



Amino

acid

SciFinder

results

CSD structures


























5 Conclusions





Table 6





Gln



respectively)








solubility



































Acknowledgments






acknowledged

References































compound [156e158]


































































338





















































































[154] T Fris

c

ic






























5 Conclusions





Table 6





Gln



respectively)








solubility



































Acknowledgments






acknowledged

References































compound [156e158]


































































338





















































































[154] T Fris

c

ic












solubility



































Acknowledgments






acknowledged

References































compound [156e158]


































































338





















































































[154] T Fris

c

ic









































































338





















































































[154] T Fris

c

ic




























































































[154] T Fris

c

ic









pharmaceutical salts and cocrystals involving amino acids a brief structural overview of the state...

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