Pharmaceutical cocrystals_ along the path to improved medicines
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Showcasing research and insights from the crystal engineering research group at the University of Limerick, Ireland and Moderna Therapeutics, USA, a pioneer in messenger RNA therapeutics.
Pharmaceutical cocrystals: along the path to improved medicines
Pharmaceutical cocrystals can enable better medicines by improving the physicochemical properties of drug substances in a manner that is not always readily achieved when using traditional approaches to pharmaceutical materials. That they have gone from an underexplored class of crystalline solids to the lab bench and now to the bedside in just over a decade is documented in this feature article.
See Michael J. Zaworotko et al Chem. Commun., 2016, 52, https://www.wendangku.net/doc/364629617.html,/chemcomm
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Pharmaceutical cocrystals:along the path to improved medicines
Naga K.Duggirala,a Miranda L.Perry,a O
¨rn Almarsson b and Michael J.Zaworotko*a Cocrystals,a long known but understudied class of crystalline solids,have attracted interest from crystal engineers and pharmaceutical scientists in the past decade and are now an integral part of the pre-formulation stage of drug development.This is largely because cocrystals that contain a drug molecule,pharmaceutical cocrystals,can modify physicochemical properties without the need for covalent modifica-tion of the drug molecule.This review presents a brief history of cocrystals before addressing recent advances in design,discovery and development of pharmaceutical cocrystals that have occurred since an earlier review published in 2004.We address four aspects of cocrystals:nomenclature;design using hydrogen-bonded supramolecular synthons;methods of discovery and synthesis;development of pharmaceutical cocrystals as drug products.Cocrystals can be classified into molecular cocrystals (MCCs)that contain only neutral components (coformers)and ionic cocrystals (ICCs),which are
comprised of at least one ionic coformer that is a salt.That cocrystals,especially ICCs,o?er much greater diversity in terms of composition and properties than single component crystal forms and are amenable to design makes them of continuing interest.Seven recent case studies that illustrate how pharmaceutical cocrystals can improve physicochemical properties and clinical performance of drug substances,including a recently approved drug product based upon an ICC,are presented.
Introduction
An awakening has occurred in the first part of the 21st century to the potential of crystal engineering and materials science to optimise performance of drug products.The phrase
‘‘Molecules,
a
Department of Chemical &Environmental Sciences and Bernal Institute,University of Limerick,Limerick,Republic of Ireland.E-mail:xtal@ul.ie b
Moderna Therapeutics,Inc.200Technology Square,Cambridge,MA 02139,
USA
Naga K.Duggirala
Naga Kiran Duggirala was born in Kandrika,India.He obtained his Master’s degree in organic chemi-stry from Andhra University.After,he joined Dr Reddy’s Laboratories where his work mainly focused upon screening and development of novel solid forms.Currently he is a PhD student at University of Limerick,supervised by Professor Michael Zaworotko.His current research aims toward crystal engineering of pharmaceutical cocrystals,with particular
emphasis on ionic cocrystals of lithium and chloride salts.His broad research interests include formulations,developing oral dosage forms and drug
delivery.
Miranda L.Perry
Dr Miranda Perry is currently a senior postdoctoral fellow at the University of Limerick.She received her degrees in Chemistry from the University of West Florida in 2004(BSc)and University of South Florida in 2009(PhD).Her graduate work,supervised by Prof.Mike Zaworotko,addressed the supramolecular assembly of cocrystals and their role in solid-state synthesis.From 2009to 2014she worked as a research scientist at Thar Pharmaceuticals
where her work involved the development of novel crystal forms of pharmaceuticals,specifically cocrystals,salts,and polymorphs.Current research interests include developing novel multi-component pharmaceutical materials (MPMs)via a crystal engineering based approach.
Received 2nd October 2015,Accepted 2nd November 2015DOI:10.1039/c5cc08216a
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Materials,Medicines’’,which has been the banner of conferences since 2007,2succinctly reflects the idea that drugs are formed from a convergence of synthetic chemistry,materials science and engineering coupled with pharmacological and clinical evalua-tion.Drug discovery and development can therefore be regarded as being comprised of three distinct stages that might be termed ‘‘molecules,materials and medicines’’,respectively 2(Scheme 1).The ‘‘molecules’’stage includes medicinal chemistry for the discovery of new chemical entities along with biological and pharmacological screening for activity.The ‘‘materials’’or pre-formulation stage addresses the discovery of a drug sub-stance,normally a solid,suitable for use as a material in a drug product.The ‘‘medicines’’or formulation stage combines this drug substance (also known as the active pharmaceutical ingredient,API)with inactive ingredients,excipients,to a?ord
a drug product.The materials stage came to the fore in the 1990’s after regulatory bodies issued guidance that in e?ect mandated characterisation of the solid forms of a drug sub-stance.3Intellectual property issues,highlighted by litigations involving ranitidine hydrochloride,Zantac s ,4which at the time was the world’s best-selling drug product,further emphasized the importance of pre-formulation research.This was com-pounded by performance problems caused by a previously undiscovered polymorph of ritonavir,in a capsule formulation marketed under the trade name Norvir s .The reduced solubility of this polymorph resulted in market withdrawal and sub-sequent reformulation.5
The motivation to create new solid forms of drug molecules is therefore a consequence of how important drug substances are to the performance of orally administered drug products,the heart of which is almost always a crystalline solid.6It should be noted that amorphous solids have also been selected for use in drug products,but the need to meet specifications in terms of thermodynamic stability,purity and processing means that crystalline drug substance are generally preferred.7That the physicochemical properties of a crystal form are inherently dependent upon the composition and the crystal packing of the molecules/ions means that exerting control over composition and crystal packing could in turn lead to control over properties.It is in this context that crystal engineering 8research on pharma-ceutical cocrystals started in earnest with the main goals of improving the stability and/or the solubility of drug substances.1,9Crystal forms of drug molecules,as would be expected,are a microcosm of molecular solids in general.In particular,they can be either single-component or multi-component.
Single-component
Scheme 1The three stages of early drug discovery and development:identify a molecule that is biologically active;create a material suitable for use in a drug product;formulate the material into a medicine with
excipients.
O
¨rn Almarsson Dr O
¨rn Almarsson is currently the head of formulation and delivery technologies at Moderna,a pioneer in mRNA therapeutics,based in Cambridge,MA.He received his BSc in chemistry from the Univer-sity of Iceland in 1988,and PhD in bio-organic chemistry from the University of California at Santa Barbara in 1994from the laboratory of Prof.Thomas C.Bruice.Following a post-doctoral stint in biotechnology at MIT with Prof.Alexander Klibanov,
Dr Almarsson joined Merck Research Laboratories in Pharmaceutical R&D.Over a 20year career in pharmaceuticals and biotechnology,his areas of interest have included drug delivery,preformulation,crystalline compounds including pharmaceutical cocrystals,biopharmaceutical performance and stabilization of drugs in
formulation.
Michael J.Zaworotko
Dr Mike Zaworotko currently serves as Bernal Chair of Crystal Engineering &Science Foundation of Ireland Research Professor in the Department of Chemical and Environmental Sciences at the University of Limerick,Ireland.He was born in Wales in 1956and received his BSc and PhD degrees from Imperial College (1977)and the University of Alabama (1982),respectively.He served as a faculty member at Saint Mary’s University,Nova
Scotia,Canada,from 1985–1998,at University of Winnipeg,Canada from 1998–1999and at the University of South Florida,USA,from 1999–2013.Research activities have focused upon fundamental and applied aspects of crystal engineering since 1990.Currently,metal–organic materials (MOMs),especially microporous and ultramicro-porous sorbents,and multi-component pharmaceutical materials (MPMs)such as cocrystals,hydrates and ionic cocrystals are of particular interest.He currently serves as Associate Editor of the ACS published journal Crystal Growth &Design.
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crystals provide limited opportunity to modulate the physico-chemical properties of a compound since they are limited to polymorphs,which tend to exhibit only subtle changes in physicochemical properties.10Indeed,the solubility di?erence between two polymorphs is typically less than two-fold.Multi-component crystals,however,are a di?erent story.They can be stoichiometric or non-stoichiometric and encompass hydrates,solvates,salts,solid solutions (mixed crystals),inclusion com-pounds and cocrystals (Scheme 2).However,the development of multi-component crystalline drug substances presents addi-tional challenges vs.single component variants.For example,physical stability can be an issue for solvates,hydrates or inclusion compounds.11Hydrates,which have been termed a ‘‘nemesis to crystal engineering’’,12are of particular relevance,thanks to the ubiquity of water vapour.However,that they can exhibit variable stoichiometry and low thermal stability,often works against their use in drug products.13Nevertheless,hydrates have been selected and developed for use in marketed drug products.14A solvate might also su?er from poor stability to elevated temperature or humidity,making it an unlikely candidate for a drug product.15Salts are a well-established approach to generate novel solid forms with improved physico-chemical properties.16The primary drawback of salts is that they are limited to API’s that contain ionisable moieties.
Crystalline solid solutions (mixed crystals)could enable a continuum of physical properties because of their variable stoichiometry,but they are not generally amenable to design and preparation of reproducible phases is nontrivial.17In principle,cocrystals do not su?er from the limitations of the other classes of multi-component crystalline solid mentioned above.Further,that they can be designed using crystal engineer-ing approaches means that suitable coformers can be rationally selected from libraries of hundreds or even thousands of potential cocrystal formers.Herein we address the evolution of pharmaceutical cocrystals since 2004.
History and nomenclature
Although cocrystals are long known,there was little consensus concerning the scope of the term cocrystal until a recent perspec-tive authored by 46scientists in the field.18According to the perspective ‘Cocrystals are solids that are crystalline single phase materials composed of two or more di?erent molecular and/or ionic compounds generally in a stoichiometric ratio which are neither solvates nor simple salts .’If at least one of the coformers is an API and the other is pharmaceutically acceptable,then it is recognized as a pharmaceutical cocrystal.
1
Scheme 2Possible crystalline forms for an API:(a)and (b)polymorphs;(c)solvate/hydrate;(d)salt;(e)molecular cocrystal;(f)ionic cocrystal;(g)non-stoichiometric inclusion compounds including channel hydrates,solvates;(h)solid solutions (mixed crystals).
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The notion of classifying cocrystals based upon the type of coformers dates back to 1922and Paul Pfei?er.19In 2009,Stahly reported examples of cocrystals containing inorganic components.20Our research group has also classified cocrystals as ‘‘molecular’’or ‘‘ionic’’depending on the nature of the coformers.Molecular cocrystals (MCCs)contain two or more di?erent neutral coformers in a stoichiometric ratio and are typically,but not always exclusively,21sustained by hydrogen bonds or halogen bonds.Most reported pharmaceutical cocrystals fall into this category.The term ‘ionic cocrystal’was coined by Braga’s research group in 2010.22Ionic cocrystals (ICCs)are typically sustained by charge assisted hydrogen bonds and/or coordination bonds (if metal cations are present).Thus,some ICCs could also be classified as coordination https://www.wendangku.net/doc/364629617.html,rge families of ICCs include acid salts 23(cocrystals containing a carboxyl-ate salt and carboxylic acid)and conjugate acid–base cocrystals (cocrystals containing an ion and its neutral counterpart 24).Ionic cocrystals (ICCs)
ICC’s can be traced back to at least 1783when Rome
`de I’Ise observed a habit change in NaCl when crystallised from aqueous urea.25Bunn (1933)26and Seifert (1937)27subsequently attributed this habit modification to the adsorption of urea on certain crystal faces of NaCl.Bunn also noted that ‘‘There is one complica-tion;in the aqueous system there is a compound NaCl áCO(NH 2)2áH 2O,the structure of which is not known ’’.In 1950,Kleber et al.28detailed the morphology and optics of this compound before Palm and MacGillavry isolated colourless,transparent crystals from slow evaporation of an equimolar solution of sodium chloride and urea.29Single-crystal X-ray crystallographic analysis revealed that the compound in question is a 1:1:1ICC of NaCl,urea and water (Fig.1).A related family of ICCs is comprised of sodium and calcium salts and sugars,a noteworthy example being NaCl and glucose,first reported by F.V.Kobell in 1843.30
ICCs based upon carboxylic acids and carboxylate salts were first reported in 1853by Gerhardt,who studied the compound formed from cooling an alcohol solution containing stoichio-metric amounts of potassium hydrogen benzoate and benzoic acid.31The composition of this ICC was confirmed in 1954.32In a subsequent review by Speakman,this family of ICCs was classified as ‘acid salts’23and he noted that ‘in some cases an acid salt is more easily made than the neutral salt;it may crystal-lize preferentially when one is trying to prepare the neutral salt ’.23Speakman explored acid salts extensively through X-ray and neutron di?raction studies and suggested that they could be
further classified into two types depending upon the nature of the carboxylate ion.In type A,the proton is shared between carboxyl-ates (Fig.2a)whereas in type B the proton is associated with only one oxygen atom,i.e.it is a carboxylic acid (Fig.2b).The systematic study of Speakman salts ultimately a?orded an understanding of the structural features of short,strong hydrogen bonds.
Improved solubility of ICCs was also addressed in early litera-ture:phenylquinoline carboxylic acid with pyrazolones,‘molecular compounds ’;33streptomycin acid salts with alkaline earth metal halides,‘complex salts ’;34theophylline with sodium salts such as sodium acetate,sodium salicylate and sodium glycinate.35Clinical trials conducted upon theophylline–sodium glycinate involved 4300patients over 18months and indicated that the ICC produced a typical theophylline response.Pharmaco-dynamics studies in a rat model revealed that the LD 50of theophylline and the ICC are 200mg kg à1and 350mg kg à1,respectively,suggesting decreased toxicity for the ICC.Hoffmann-La Roche Inc.subsequently reported the ICC of theophylline (Tp)and magnesium (Mg)salicylate (S)with the formula Tp 2MgS 2á5H 2O.36This ICC was crystallized using magnesium salicylate (0.5–2.0mol)and theophylline (1.0mol).
Another ICC that demonstrated improved performance involved a tetracycline,a class of broad spectrum polyketide antibiotics that tend to exhibit low solubility.Reverin,a derivative of tetracycline,was found to exhibit increased solubility vs.tetracycline but also increased toxicity.37Two ICCs or ‘additional complexes ’,tetracycline–sodium methylene salicylate and chlorotetracycline-sodium methylene salicylate,were administered as distilled water solutions to albino mice.The ICC was found to be less toxic (LD50:375mg kg à1)vs.Reverin (225mg kg à1).
A patent filed by George and Ernest in 1971,claimed 56ICCs formed by 3-isothiazolones and metal halides as ‘metal salt complexes ’and reported improved thermal stability vs.the corresponding isothiazoles.38For instance,5-chloro-2-methyl-3-isothiazole and its hydrochloride salt undergo 30%and 58%decomposition,respectively,at 501C whereas the CaCl 2ICC was found to be thermally
stable.
Fig.1(a)Sodium cation coordination environment and (b)1D chain observed in hydrated sodium chloride urea
ICC.
Fig.2Examples of Speakman type A and type B acid salts:(a)potassium hydrogen bis(4-flourobenzoate)and (b)potassium hydrogen bis(3,5-dinitro-benzoate).
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ICCs based upon organic cation halides were studied by Childs et al.who invented fluoxetine hydrochloride ICCs with a series of carboxylic acid coformers.39The ICC of fluoxetine hydrochloride with benzoic acid is shown in Fig.3.Modulation of dissolution rate with respect to fluoxetine hydrochloride was reported for this family of ICCs.Saxagliptin hydrochloride,Onglyza s ,exists as a monohydrate that converts to a chemi-cally unstable dihydrate during a coating process.To overcome this problem,Enantia synthesized and patented novel ICCs of saxagliptin hydrochloride.40Molecular cocrystals,(MCCs)
The MCC of quinone and hydroquinone,quinhydrone,was
reported in 1844by Wo
¨hler.41The composition was not con-firmed by single-crystal X-ray analysis until the 1960’s when it was revealed to be a 1:1MCC sustained by a C Q O áááH–O supramolecular heterosynthon (Fig.4).42An early example of an MCC with pharmaceutical utility was patented by von Heyden et al.,who claimed compositions of barbiturates with 4-oxy-5-nitropyridine,2-ethoxy-5-acetaminopyridine,N -methyl-a -pyridine and a -aminopyridine.43
Nomenclature of MCCs was inconsistent in the early litera-ture:‘molecular organic compounds ’was used by Buehler and Heap to describe MCCs of 1,2-dinitrotoluene,2,4-dinitrobenzene and 2,4-dinitrophenol with amino derivatives of naphthalene,benzidine and aniline;44‘organic molecular compounds ’was used by Anderson in 1937.45Use of MCCs (termed ‘complex ’46)to improve the performance of a drug substance was exempli-fied by digoxin and hydroquinones.Digoxin is indicated for the treatment of mild to moderate heart failure but its dissolution rate and bioavailability are low.Higuchi and Ikeda found that the solubility of digoxin increases in the presence of hydroquinone.46
Bochner et al.47later conducted clinical trials in humans that compared MCCs of digoxin with commercially available tablets of digoxin.These studies revealed that peak serum digoxin concen-trations for the MCC were achieved faster than commercial digoxin tablets.Even as early as 1974,the potential use of MCCs to improve the clinical performance of low solubility drugs was envisioned by the authors who stated that ‘the principle of complexing a drug with substances such as hydroquinone to enhance the dissolution might be applied to other medication whose absorp-tion is erratic following poor in vivo dissolution.’
Ambiguity concerning whether a compound should be classified as a salt or a cocrystal is a topical subject 48but was also discussed as far back as the 1930’s.Two MCCs from 1934,were initially considered to be salts formed between urea and oxalic acid (in 1:1and 1:2stoichiometry).49Subsequent analysis by Harkema et al.revealed that they are addition compounds,i.e.MCCs,(CSD refcodes:UROXAL 50and UROXAM 51).
Another term that has been used to describe MCCs is ‘hydrogen bond complex ’.Hoogsteen prepared such MCCs to provide evidence for the existence of purine–pyrimidine base pairs in DNA.The MCC between 9-methyladenine and 1-methylthymine 52exhibits what is now known as a Hoogsteen base pair.The crystal structure is sustained by 2-point hydrogen bonds (N–H áááO and N–H áááN)as shown in Fig.5.It was later determined by Margaret Etter that this Hoogsteen base pair is persistent even in the presence of a third competing coformer by solid-state grinding.53
The term cocrystal was not popularized until the 1990’s,due in large part to Etter,who extensively studied hydrogen bonds as design elements for the preparation of multi-component crystals.Her research contributions to the field of cocrystal design include concepts that are still used today for determining the propensity for hydrogen bond interactions.54Nevertheless,despite increasing use of the term cocrystal in the crystal engineering field,some researchers have coined di?erent terms.For example,Pekker et al.reported ‘heteromolecular crystals ’of fullerene and cubane in 2005.55
In summary,ICCs have been known as acid salts,molecular compound,complex salt,additional complexes,metal salt com-plexes and adduct.MCCs have been termed molecular
organic
Fig.3The discrete assembly that is sustained by charge assisted hydrogen bond interactions in fluoxetine hydrochloride–benzoic
acid.
Fig.4Illustration of the 1D chain sustained by O–H áááO hydrogen bonds in hydroquinone–quinone,
quinhydrone.
Fig.5The Hoogsteen base pair observed in the MCC of 9-methyl adenine and 1-methyl thymine is sustained by N–H áááO and N–H áááN hydrogen bonds.
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compounds,organic molecular compounds,addition com-pounds,mixed crystals,complexes,hydrogen bonded com-plexes and heteromolecular crystals.
Design of pharmaceutical cocrystals
The design and synthesis of new cocrystals may appear to be established given that thousands of cocrystals have been synthesized.However,the complexity of most drug molecules requires an understanding of intermolecular interactions in a competitive hydrogen bond environment,i.e.crystal engineer-ing.In this section,we address how crystal engineering has been applied to cocrystal design.
Crystal engineering –supramolecular chemistry in the solid state
The term crystal engineering can be traced back to 1955and Pepinsky.8His ideas were subsequently implemented by Schmidt’s group to control organic solid-state photochemical reactions.56Crystal engineering further evolved in the 1980’s largely thanks to Desiraju.57Today,crystal engineering has evolved to encompass a broad range of chemical species ranging from drug molecules (especially in the context of cocrystals)to transition metal clusters or cations (especially in the context of coordination networks 58).A unifying theme that cuts across chemical types is that crystal structures are treated as if they are sustained by a series of repeating supramolecular inter-actions.The first step in a crystal engineering experiment is therefore to understand the interactions that sustain and direct crystal packing.Etter developed a set of empirical rules to determine the propensity for hydrogen bonding given various donor/acceptor combinations.Etter’s rules included the follow-ing:the best proton donor will hydrogen bond to the best proton acceptor;six membered ring intramolecular hydrogen bonds are favourable.59Etter’s rules are applicable to cocrystals and are particularly useful when there are multiple functional groups capable of hydrogen bonding.Etter also pioneered the use of graph set theory to describe hydrogen bonded motifs in crystals.60However,this type of analysis has been superseded by supra-molecular synthons,which are functional group specific.61Cocrystals and supramolecular synthons
There are two main types of supramolecular synthons:supra-molecular homosynthons between the same complementary functional groups (e.g.carboxylic acid dimers);supramolecular heterosynthons between di?erent but complementary func-tional groups (Fig.6).62Supramolecular heterosynthons are of particular relevance to cocrystal design since,if the functional groups of a supramolecular heterosynthon are in di?erent coformers,they can be the driving force for cocrystal formation.Carboxylic acid–amide,63carboxylic acid–aromatic nitrogen,64alcohol–aromatic nitrogen,65and alcohol–amine 66supramolecular synthons have all been widely studied in this context.
During 2003–2004four pharmaceutical cocrystal papers were published by three groups emphasizing the key role that
crystal engineering can play in cocrystal design.Indeed,the first two words in each of these papers were ‘‘crystal engineering’’.63f ,67,62,39Indeed,it was these four articles that spurred the development and publication of the precursor 1to this review.In a sense,these papers could be called the beginning of the modern era of cocrystals.Drug molecules typically contain multiple hydrogen bond donor and acceptor groups and so they are ideally suited to the formation of cocrystals.This creates a challenge to crystal engineers since understanding the hierarchy of these functional groups in the presence of other functional groups is key to controlling not just the stoichiometry of cocrystals,but also their existence.Addressing this matter is not usually as simple as it may sound.For example,carboxylic acids would be considered to be better hydrogen bond donors than phenols based upon p K a .However,
this is not necessarily the case as we 68and Aakero
¨y 69have reported.Further,although the CSD contains 4700000entries and continues to grow rapidly,this does not mean that the CSD provides statistically valid hit lists to address even relatively simple permutations of donors and acceptors.Therefore,sys-tematic supramolecular synthon hierarchy studies remain an important aspect of crystal engineering and cocrystal design.Molecular surface electrostatic potentials and density functional theory calculations (DFT)are also useful tools to support cocrystal design.Another approach to predict cocrystal formation,initially reported by Galek et al.70utilized the CSD to generate a statistical analysis of hydrogen bond propensity between drug molecule and coformer.
Hierarchy of supramolecular synthons
Several research groups have published studies that delineate donor/acceptor hierarchies involving one or more of the following moieties:carboxylic acids,carboxylates,amides,aromatic nitro-gens,alcohols,phenols,cyano groups,cyanooximes.One of our studies addressed the hierarchy of supramolecular synthons between carboxylic acids and aromatic nitrogens in the presence of phenols.71Interestingly,both carboxylic acid–aromatic nitrogen and phenol–aromatic nitrogen supramolecular
heterosynthons
Fig.6Supramolecular homosynthons (a)carboxylic acid homosynthon exist as dimer (b)amide homosynthon exist as dimer;supramolecular heterosynthons (c)carboxylic acid–amide heterosynthon (d)carboxylic acid–pyridine heterosynthon.
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were encountered.This observation suggests that carboxylic acid and phenol groups are competitive with respect to forming supramolecular heterosynthons with aromatic nitrogen atoms.
Aakero
¨y and co-workers also examined hydrogen bond hierarchy between carboxylic acids,phenols and basic nitrogen atoms.69Two nitrogen atoms with different basicity were exploited to assess interactions.Electrostatic surface potential calculations indicated that phenolic –OH moieties would be preferred to carboxylic acid moieties.Indeed,carboxylic acids consistently formed supramolecular heterosynthons with the second best basic nitrogen.
In another of our hierarchy studies we used ICCs as a vehicle to examine the propensity for chloride anions to interact with carboxylic acids vs.phenols.68Crystal structures and DFT/lattice energy calculations suggest that phenol to chloride anion interactions persist over carboxylic acid to chloride anion interactions.Supramolecular synthon hierarchy of alcohols vs.aromatic nitrogen atoms in the presence of a cyano moiety,72hydrogen bonds between carboxylates and weakly acidic hydroxyl moieties in cocrystals of zwitterions 73and phenols to the most basic acceptor in the presence of cyanooxime have also been addressed.74The above hierarchy studies are consistent with Etter’s ‘‘best hydrogen bond donor to best acceptor’’guideline.These studies have collectively provided insight into donor/acceptor hierarchy and it is likely that they can be generally applied to cocrystal design.However,many drug molecules fall outside the realm of current studies and the information archived in the Cambridge Structural Database,CSD,75requiring that new hierarchy studies to be conducted.A flowchart that details a general process for delineation of supramolecular synthon hierarchy is presented in Scheme 3.
Advances in pharmaceutical cocrystal development since 2004
The surge of interest in pharmaceutical cocrystals within the past decade has been driven by their potential utility as alternative drug substances with improved physicochemical properties.How-ever,developing a drug substance into a drug product is not a trivial task.In general,the development of a pharmaceutical cocrystal as the active ingredient in a drug product can be separated into eight stages (Scheme 4).Stage 1:design +coformer selection
Selection of a library of complementary coformers for a parti-cular drug molecule is a critical aspect of cocrystal design and screening.A suitable coformer in the context of pharmaceutical cocrystals must be inherently safe enough for use in a drug product.The Priority-based Assessment of Food Additives (PAFA)database contains chemical and toxicological informa-tion for ca.2000substances,including those with the Generally Recognized As Safe (GRAS)designation,76which can be directly added to food.Including an additional 1000substances that are considered safe food additives,there are ca.3000compounds that constitute the Everything Added to Food in the United States
(EAFUS)database.The selection of a library of coformers (typically 40–50)that are likely to form cocrystals for a given API based upon supramolecular compatibility is the first step in discovery of a pharmaceutical cocrystal.Other approaches that have been used for library development include the following:Fabian’s method 77(based upon shape and polarity of coformer with respect to API);lattice energy calculations;78virtual cocrystal screening (based upon molecular electrostatic potential surfaces (MEPS));79the conductor-like screening model for real solvents (COSMO-RS).80Each approach has its merits and could be used independently or coupled with others.Stage 2:discovery
Once a library of coformers has been selected,then the next stage is discovery.Traditional methods used to discover cocrystals include slow solvent evaporation,slurry mediated transformation and mechanical grinding (both neat and solvent-drop or liquid assisted).81More recently,polymer assisted grinding has been reported as an alternative to liquid assisted grinding to improve the rate of formation of cocrystals.82Other methods that are known to facilitate the formation of cocrystals include ultrasound assisted solution cocrystallization,83high-throughput screening,84microfluidic approach 85and supercritical fluid technologies.86Thermal and microscopic methods have been also utilized for identification of new cocrystals.Berry et al.87demonstrated the use of hot stage microscopy to identify cocrystal phases of nicotinamide with seven API’https://www.wendangku.net/doc/364629617.html,putational approaches have advanced to the stage where stable cocrystals can be predicted in advance of being prepared experimentally.However,this does not mean that they can be easily obtained through traditional methods.Alternative techniques such as heteronuclear seeding have proven successful at the generation of such an elusive MCC,that of ca?eine–benzoic acid.88In short,comprehensive screen-ing including multiple techniques should be conducted to enable the discovery of new cocrystals.It is perhaps appropriate to paraphrase McCrone’s statement concerning polymorphism 89and assert that the number of cocrystals that will ultimately
be
Scheme 3A general approach to delineate synthon hierarchy among various functional groups,copyright.
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discovered will only be proportional to the amount of time and money devoted to researching them.Stage 3:characterization
The primary techniques used to characterize novel cocrystals are those used generally for crystal forms including powder X-ray di?raction (PXRD),single-crystal X-ray di?raction (SCXRD),di?erential scanning calorimetry (DSC),thermogravimetric ana-lysis (TGA),infrared and Raman spectroscopies and solid-state nuclear magnetic resonance (ssNMR).SCXRD confirms compo-sition but single crystals are not necessarily always available from the discovery stage.In such situations,structure solution from microcrystalline powder samples or advanced spectroscopic techniques has been demonstrated to be e?ective for cocrystals.For example,Lapidus et al.90determined crystal structures of 10cocrystals from high-resolution synchrotron X-ray powder di?raction.Spectroscopic methods have also been applied to identify the cocrystal phase during the discovery.Desiraju identified MCCs sustained by amide dimers from diagnostic N–H áááO bands in their IR spectra.91Raman spectroscopy has also been used to study cocrystals,including their formation during high-throughput slurry screening and to distinguish between a cocrystal and a physical mixture in formulated tablets.92Vogt et al.93demonstrated that ssNMR can be effec-tive for the characterization of cocrystals by diagnosing hydro-gen bonding and local conformational changes by 1H–1H,1
H–13C and 19F–13C coupling.Maruyoshi et al.94identified COOH áááN arom and CH arom áááO Q C interactions in indometha-cin–nicotinamide by using 2D 1H double quantum and 14N–1H and 1H–13C heteronuclear magic angle spinning.Terahertz time-domain-spectroscopy has also been used to distinguish between chiral and racemic MCCs of malic acid and tartaric acid with theophylline.95Near-edge X-ray absorption fine struc-ture (NEXAFS)and X-ray photoelectron spectroscopy (XPS)were applied to differentiate between a salt and a cocrystal.96Stage 4:properties
A major motivation for the development of new solid forms of drug molecules is to improve those physicochemical properties that are of critical relevance to their performance as drug substances.
These include aqueous solubility/dissolution rate and physical stability.Currently,there are 4100studies of cocrystals that have demonstrated improved solubility and/or dissolution rates and this subject.9Improved physical stability,chemical stability and manufacturability via cocrystallization have also been addressed.Anhydrous ca?eine and theophylline readily convert to their respective hydrated forms.Jones’research group 97prepared MCCs of ca?eine and theophylline with oxalic acid and they were found to exhibit superior physical stability vs.the anhydrous crystal forms when exposed to accelerated stability tests (401C/75%RH).Vitamin D 3cocrystals have also been studied in the context of chemical stability.98Vitamin D 3is widely used in the food and nutraceutical industries but is chemically unstable because it is susceptible to topochemical reaction.MCCs of vitamin D 3with cholesterol and cholestanol sustained by O–H áááO–H supramolecular synthons were sub-jected to accelerated stability testing for 6months.The assay value of vitamin D 3decreased to 4.4%under these conditions whereas the MCCs afforded 97.6%and 96.6%assay values,respectively.
MCCs containing paracetamol and oxalic acid,theophylline,naphthalene and phenazine were pressed into tablets and subjected to mechanical stress.The MCCs were found to exhibit greater tensile strength than paracetamol.99The for-mulation of drug substances generally requires that the melting point is high enough to avoid plastic deformation.In a recent patent application from UCB Pharma an ICC of (2S )-2-2[(4S )-4-(2,2-difluorovinyl)-2-oxopyrrolidinyl]butanamide with MgCl 2and H 2O (2:1:4stoichiometry)was claimed with a melting point ca.501C higher than that of the pure API.100Stage 5:pharmacokinetics
A recent review by Shan et al.101addressed the e?ect of cocrystallization upon API pharmacokinetics (PK).64cocrystals representing 21API’s a?orded 76PK studies.80%of the APIs are classified class II (low solubility,high permeability)accord-ing to the Biopharmaceutics Classification System (BCS).102This is unsurprising given that improving solubility has moti-vated the study of pharmaceutical cocrystals.Analysis of the PK results suggests that solubility enhancements generally
result
Scheme 4Illustration of various states and advances at each stage along the drug development pathway of pharmaceutical cocrystals.
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in increases in area under the curve (AUC).The impact of cocrystals upon AUC can be significant,ranging from ca.10.2-fold decrease to ca.28.4-fold increase.C max changes ranging from a 4-fold decrease to a 44-fold increase have been observed.Most cocrystals,however,were found to exhibit less significant changes in AUC and C max .Variations in PK after dosing di?erent drug substances can a?ect the safety,e?cacy and clinical performance of a drug product.Further,if the application for the API is fast onset of pain relief,then the ability to manipulate specific PK para-meters becomes critical.For instance,to develop an API for acute pain relief,the time required to reach the e?ective concentration must be short.Weyna et al.103illustrated how meloxicam,an NSAID indicated for rheumatoid arthritis and postoperative pain,is impacted by cocrystallization.Meloxicam is a BCS class II API with a 4–5hour T max .MCCs of meloxicam were synthesized and PK studies in rats revealed an earlier onset of action,suggesting that a T max of o 30min is possible for some of the studied MCCs.Stage 6:formulation
Before a cocrystal can be introduced into a drug product it is necessary to formulate the cocrystal.That cocrystals are typically sustained by hydrogen bonds means that their stabi-lity in the presence of excipients which also contain hydrogen bonding groups becomes a risk.Remenar et al.104and Alhalaweh et al.105highlighted the use of excipients to alter the rate of dissolution and capture the maximum potential of celecoxib–nicotinamide and indomethacin–saccharin MCCs,respectively.
Huang and Rodr?
′guez-Hornedo 106manipulated the micellar solubilisation and stability of cocrystal components in solution.Abourahma et al.107studied the robustness of theophylline p -hydroxybenzoic acid in the presence of additives during solvent-drop grinding experiments.Their results indicate that the cocrystal is robust in the presence of additives that contain carboxylic acid,amide and phenol functional groups but not in the presence of acetamide.Arora et al.108recently demon-strated that the carbamazepine–nicotinamide MCC can be formed in a formulated tablet,a phase change attributed to release of lattice water from an excipient (dibasic calcium phosphate dihydrate).
A pharmaceutical cocrystal sustained by halogen bonds was recently reported by Baldrighi et al.109The commonly used preservative 3-iodo-2-propynyl-N -butylcarbamate exhibits unfavour-able manufacturing properties,including a low melting point and a tendency of particles to stick and clump together.Four cocrystals were prepared and SCXRD experiments revealed that three of the cocrystals are sustained by halogen bonds involving pyridyl moieties.The fourth cocrystal is an ICC of CaCl 2.Melting points were observed to increase in a manner that correlates with the coformer.The clumping tendency of 3-iodo-2-propynyl-N -butylcarbamate was improved,especially in the case of the ICC.
Given that formulation of cocrystals is a necessary stage in drug development,it is likely that studies addressing formula-tion issues will increase in frequency.
Stage 7:process and scale-up
The traditional solution methods (solvent evaporation/slurry)used for cocrystal discovery can present challenges for large-scale manufacturing since we are dealing with at least a ternary phase diagram (TPD).Indeed,cocrystallization from solution could even be viewed as counterintuitive since this is the preferred approach to purify single component molecular compounds,in general,and APIs,in particular.However,if a cocrystal is thermo-dynamically favoured vs.single component crystals and the TPD is well delineated,then solution crystallisation is suitable to process cocrystals.For example,by understanding the TPD,Sheikh et al.110prepared carbamazepine–nicotinamide with 490%yield in a 1L vessel.
It is also possible that cocrystallization can address pro-blems associated with purification of APIs.A kinase inhibitor in development at Sanofi forms unstable solvates.Approaches such as chromatography,adsorption of impurities and multiple crystallizations a?orded the API but with only ca.90%purity.A purity of 99.1%was achieved using a process that involved cocrystallization of the API with benzoic acid.The process was successfully transferred to plant scale,a?ording a 10kg batch size.111Myerson’s research group has also used cocrystalliza-tion for purification of an API.By complexing an impurity in amoxicillin/amino acid solutions they improved the purity of amoxicillin trihydrate.112Cocrystallization has also been used to separate stereoisomers.Khan et al.113demonstrated selective separation of quinidine from its stereoisomer by forming MCCs with methylparaben.The authors attribute the separation to methylparaben serving as a molecular hook which sustains O–H áááN supramolecular heterosynthons with only one isomer of quinidine as shown in Fig.7.
In a study by Hickey et al.114the authors reported cocrystal scale-up in 30gram scale by cooling from alcoholic solution The challenge for solution crystallization is the likely incon-gruent solubilities of molecular components.Thus,the less soluble compound in solution tends to supersaturate and crystallize first.Rodriguez-Hornedo and her research group addressed this issue through reaction crystallization by focusing upon the kinetics of cocrystallization and analysis of stability domains of cocrystals in solution.106,115
A commonly used and eco-friendly method to prepare cocrystals at lab-scale is solid-state grinding (mechanochemistry).The main challenges with this method are high mechanical stress and the di?culty in achieving a homogeneous mix for larger scale processes.Alternatives to grinding include twin-screw extrusion (AMG517-sorbic acid 116)and resonant acoustic mixing (carbama-zepine–nicotinamide 117).Resonant acoustic mixing can enable preparation of volumes greater than 200L and requires the addition of only small amounts of solvent during mixing.Synth-esis of such quantities does,however,often require slurrying to obtain the desired cocrystal in high purity.Other methods used for cocrystal synthesis include super critical fluid technology,86spray drying 118and a continuous oscillatory baffled crystallizer.119Such cocrystallization methods facilitated by process analytical technology tools (PAT)are growing and could enable development of large-scale manufacturing of cocrystals.
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Stage 8:regulatory approval
The ultimate step in developing a new drug is achieving regulatory approval.However,it should be noted that intellectual property protection will have supported an investment decision at some point during development.Within the past decade there have been numerous composition of matter patents granted for cocrystals on the premise that their cocrystals satisfy the three primary criteria for issuing a patent:(1)novelty (cocrystal is a new composition of matter),(2)non-obviousness/inventiveness (the physicochemical properties and pharmacokinetic properties are di?cult to predict with any degree of certainty)and utility (the drug substance has pharmacological activity and/or improved performance vs.the corresponding single component drug substance).The pharmaceutical cocrystal patent landscape has been reviewed by Almarsson,Peterson and Zaworotko.120
In 2011the FDA released draft guidance for industry on the subject of pharmaceutical cocrystals.Within that guidance,a cocrystal was considered to be a dissociable ‘‘API-excipient’’molecular complex,a drug product intermediate,and not a new API.This distinction is important because an intermediate in a drug development process is treated very di?erently than a di?erent API.To gain product approval,the FDA also required the applicant to address two matters:
The API and excipient must completely dissociate prior to reaching the pharmacologically active site.
The API and excipient are in neutral states and do not interact by ionic https://www.wendangku.net/doc/364629617.html,e of the D p K a rule was suggested as a way to satisfy the second criterion.
In response to the FDA guidance,a perspective article was published in 2012.18To summarize,the authors opined that cocrystals should not be treated any di?erently than salts as the di?erence between a cocrystal and salt depends only upon the position of a proton that can be temperature dependent.121Pharmaceutical companies responded directly to the FDA with consensus that cocrystals should be treated as salts.That there are marketed drug substances that are considered by many to be cocrystals lends support to this argument.Ca?eine citrate,122sodium valproate–valproic acid in Depakote s 123and escitalopram
oxalate with oxalic acid 124are three such examples.The ICC of escitalopram oxalate oxalic acid is shown in Fig.8.
The path to commercialization of a pharmaceutical cocrystal in the United States remains unclear with respect to regulatory approval.Interestingly,the European Medicines Agency (EMA),which reviews and approves products in Europe,published a reflection paper summarizing their position on the subject of pharmaceutical cocrystals.125Currently,the EMA considers cocrystals to be homogeneous crystalline structures made up of two or more components in a definite stoichiometric ratio where the arrangement in the crystal lattice is not based on ion pairing.Other salient matters raised by the EMA reflection paper on cocrystals include:
Cocrystals are considered eligible for generic drug product applications in the same way as salts,solvates and amorphous solids would be.
Cocrystals are not considered as New Active Substances (NAS)unless they demonstrate di?erent safety and e?cacy profiles. Cocrystals and salts share many conceptual similarities and therefore also similar principles for documentation should be applied.
Despite the very di?erent positions taken by the FDA and EMA with respect to pharmaceutical cocrystals,that there are position documents from both agencies provides guidance to industry and attests to the growing interest in the use of pharmaceutical cocrystals in drug products.
Pharmaceutical cocrystal case studies
Seven case studies that address di?erent issues in drug devel-opment are presented herein.The relevant drug molecules are illustrated in Scheme 5.
Improved bioavailability:metaxalone
Metaxalone is the API in Skelaxin s ,which is indicated for the relief of discomfort associated with musculoskeletal pain.
126
Fig.7Illustration of O–H áááN intermolecular hydrogen bond as seen in quinidine–methylparaben
MCC.
Fig.8Observation of dioxalate anion and oxalic acid in the same crystal structure sustained by O–H áááO interactions in the marketed drug;escitalo-pram oxalate–oxalic acid ICC.A water molecule is removed for clarity.
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Nuformix has identified MCCs of metaxalone with superior properties that are currently in clinical trials.Metaxalone is a BCS class II drug 127and its oral bioavailability is greatly influ-enced by food.Attempts have previously been made to develop alternative crystalline or amorphous forms of metaxalone;128however,MCCs of metaxalone show great promise with improved bioavailability in beagle dogs.129The oxazolidone moiety in metaxalone was exploited to form MCCs with adipic acid,fumaric acid,succinic acid,maleic acid and salicylic acid.A single dose PK study in beagle dogs was conducted to compare the fumaric and succinic acid MCCs with metaxalone.The greatest plasma concen-tration (C max )was achieved after dosing the metaxalone fumaric acid MCC (3635ng ml à1).However the time to achieve maximum plasma concentration was the fastest for pure metaxalone.The area under the curve (AUC)for the metaxalone fumaric acid MCC and succinic acid MCCs were 5202ng h ml à1and 4135ng h ml à1,respectively,both greater than that of metaxalone.Formulation:danazol
The behaviour of a cocrystal during formulation is largely unknown in the public domain.However,a recent publication by Childs et al.130provide insight into a danazol cocrystal formulation.The cocrystallization and formulation of danazol,a synthetic steroid approved for endometriosis 131was addressed.With its low aqueous solubility (0.0067mg ml à1)132limiting its bioavailability,danazol is a BCS class II compound.Danazol is also non-ionisable,making cocrystallization a logical approach for improving solubility and PK performance.A MCC with vanillin was prepared that was sustained by O–H áááO and O–H áááN interactions (Fig.9).The MCC was subsequently evaluated with a variety of solubilizing agents and precipitation inhibitors to determine their effect upon performance.Intrinsic dissolution studies were conducted under non-sink conditions at 371C in fasted simulated intestinal fluid (FaSSIF)using
compressed discs of pure MCC and danazol.During the first 15minutes,the dissolution rate of the MCC was orders of magnitude greater than danazol although eventually the vanillin concentration was much greater than that of danazol,indicating crystallisation of danazol.In order to reduce or inhibit this effect,solubility studies were conducted using free flowing powder under sink and non-sink conditions.The sink condition powder dissolution study incorporated lactose to aid in the wetting and dispersion of the powder but the solubility advant-age of the MCC appeared to be hampered due to transformation to danazol at the surface.The non-sink conditions included two different excipients,a solubilizer (D -a -tocopheryl polyethylene glycol succinate,TPGS)and a crystallization inhibitor (Klucel LF Pharma hydroxypropylcellulose,HPC).The use of TPGS and HPC enabled a 5.5-fold increase in supersaturation vs.that of danazol.Taking into consideration the 10-fold increase in solubility from the MCC and the increase enabled by excipients,the solubility of the formulated MCC is close to the anticipated requirement for a human to absorb the entire 20mg kg à1dose (based upon maximum absorbable dose calculation using a 250ml volume,270minute intestinal transit time and absorp-tion value of 0.05min à1).The performance of the MCC vs.danazol was also addressed in Sprague-Dawley rats.A single oral dose (20mg kg à1danazol)of an aqueous suspension containing MCC or danazol plus lactose and PVP was administered and plasma concentrations were monitored.An additional arm of the study determined the effect of formulation (1%TPGS and 2%HPC)on the performance of the MCC and danazol.It was determined that danazol and the MCC perform best when formulated with TPGS and HPC vs.a suspension with lactose and PVP (10%bioavailability vs.8%for danazol;100%bioavail-ability vs.13%for the MCC).Considering the in vitro and in vivo data collectively,a positive correlation between the increase in dissolution and increase in absorption of danazol was observed.Improved e?cacy:tramadol hydrochloride with celecoxib Tramadol is a centrally acting synthetic opioid analgesic used to treat moderate to severe pain.133Tramadol has two chiral centres and in the marketed drug is a racemic mixture of the hydrochloride salt.The dosage of tramadol required to treat pain can be as low as 25mg day à1and is increased as needed,potentially building up to a dose of 100mg every 4to 6hours.Unfortunately,such high doses of tramadol can cause severe side e?ects.Thus there is a need for a low dose https://www.wendangku.net/doc/364629617.html,bination treatments with other COX inhibitors have shown greater e?cacy (measured through reductions in pain scores)than with a tramadol paracetamol combination.134With a goal to develop an e?ective combination dosage form,Esteve reported an ICC of tramadol HCl with celecoxib.135Celecoxib
is
Scheme 5Molecular structures of APIs in the seven selected case
studies.
Fig.91D hydrogen bonded chains observed in a danazol–vanillin MCC.
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a COX-2inhibitor selective non-steroidal anti-inflammatory drug (NSAID)used to treat osteoarthritis and acute pain.136Celecoxi
b is a BCS class II drug (7m g ml à1in water).Slow dissolution of celecoxib also contributes to its low bioavail-ability.Variations in the excipients used in the formulation of the ICC provided further enhancement in PK when compared to the marketed drug products Celebrex s and Adolonta s (celecoxib and tramadol HCl,respectively).Type A tablets consisted of Kollidon s VA 64,type B contained Soluplus s and type C contained Kollidon s VA 64without Sepitrap s 80&4000.A single dose PK study involving tablets A,B,C and concomitant administration of celecoxib and tramadol HCl was conducted on beagle dogs.The PK profile revealed that,when compared to Adolonta s ,the overall exposure (AUC 0àN )values were reduced for the formulations A,B and C by factors of 0.3,0.4and 0.9,respectively.However,similar T max values were observed for all formulations,suggesting that the novel formulations could have a better safety profile vs.Adolonta s .For celecoxib,PK parameters were much more variable with respect to formulation with type C tablets providing the greatest AUC 0àt and shortest T max ,37780ng h ml à1and 2.3hours,respectively.Celebrex s tablets had a much longer T max (14.5hours)and reached a maximum concentration of 1049ng ml à1.Therefore,the novel formulations of the ICC achieved higher plasma concen-trations and greater exposure to celecoxib vs.Celebrex s .Thus,the ICC o?ers two key benefits not attainable when the components are administered separately:(1)the safety of tramadol is improved and (2)the bioavailability of celecoxib is increased.Enhanced stability:sodium valproate with valproi
c aci
d Valproic acid is an anticonvulsant also used for th
e treatment o
f manic episodes associated with bipolar disorder.137Valproic acid (Depakene s )is a liquid at room temperature and is therefore di?cult to develop as a solid dosage form.Various salts of valproic acids includin
g the sodium,calcium and magnesium salts,were therefore prepared.138The use of calcium valproate has been discouraged due to adverse toxicological e?ects.139The magnesium and sodium salts of valproate were found to have similar pharmacological properties to that of valproic acid.140Sodium valproate is a solid at room temperature wit
h a substantially high melting point (3001C)but it is hygro-scopic.An alternative solid form,sodium valproate with valproic acid in a 1:1stoichiometric ratio (sodium valproate :valproic acid)was isolated by cooling an acetone solution of sodium valproate and valproic acid.123A stability test conducted at room temperature by exposing samples to 80%RH for 45min revealed that sodium valproate gained 17–24%weight whereas sodium divalproate exhibited no appreciable weight gain.Thus,due to its improved stability and comparable PK behaviour,sodium divalproate,marketed as Depakote s ,is the leading marketed form of valproic acid.More recently,another solid form contain-ing sodium valproate was reported.141The asymmetric unit of the new form (Fig.10)consists of 3sodium cations,3valproate anions,1valproic acid and a water molecule.Additional crystal-line forms (characterized by PXRD and FTIR)for the three component ICCs of sodium valproate and valproic acid exist.142
Improved bioavailability and stability:lithium salts
Lithium salts have a long history in medication;in the mid-1800s lithium was used in the treatment of gout and rheumatic disorders.143The modern revival of lithium began in 1949with Australian scientist John Cade,who demonstrated the clinical importance of lithium for mania.144To date,lithium is the only drug indicated for bipolar disorder that can also reduce suicidal tendencies.145Unfortunately,more widespread use of lithium is hindered by its low brain bioavailability and physical stability.To address these issues,the Braga research groups have synthesised novel ICCs of lithium.146Our research group has reported ICCs based upon lithium–carboxylate 147and lithium–hydroxyl bonds.148Inorganic anions such as chloride,bromide and nitrate afforded ICCs with square grid,diamondoid and ABW https://www.wendangku.net/doc/364629617.html,anic anions tend to exhibit square grid networks with lithium and carboxylates in 1:2stoichiometric ratios.To determine if these ICCs improve the bioavailability of lithium,a rat PK study was commissioned.149Lithium salicylate-proline (LISPRO)was administered as a single oral dose to Sprague-Dawley rats and resulted in 39%and 56%plasma and brain relative bioavailability compared to lithium carbonate (Li 2CO 3).While the relative bioavailabilities were lower for LISPRO com-pared with the reference,the attenuated plasma and brain concentrations extended the lithium presence for 48hours post dose.This low and steady concentration could be advantageous as the risk of toxicity associated with high serum levels of lithium is likely to be reduced.To address the poor physical stability of lithium salts an ICC of lithium chloride was pre-pared.148Lithium chloride was found to deliquesce at ca.11%RH (at room temperature).The ICC of lithium chloride with glucose was found to improve the physical stability of lithium chloride,making it stable past 11%RH although it gained 4%by weight at 30%RH and the ICC is hygroscopic at higher RH.These studies further demonstrate the diversity of ICCs (changing anions and coformers systematically)and
their
Fig.10The asymmetric unit of the ICC containing three sodium cations,three valproate anions,one valproic acid and one water molecule.Hydrogen atoms of valproate near the carboxylate groups are removed for clarity.
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ability to modulate relevant properties such as bioavailability and physical stability.
A pharmaceutical cocrystal in late-stage clinical development:ertugliflozin pyroglutamic acid
The diabetes drug candidate ertugliflozin belongs to the class of SGLT-2inhibitors,which promote excretion of glucose into urine and thus aid in the treatment of diabetes.Ertugliflozin reportedly 150did not exist in a suitable crystal form for devel-opment until the cocrystal approach was employed to improve physicochemical properties.L -Pyroglutamic acid (also known as 5-oxo-proline)qualifies as a pharmaceutically acceptable choice given its occurrence in proteins.16b The crystal structure of ertugliflozin-L -pyroglutamic acid (1:1)was published in 2014(Fig.11).151This MCC material is the basis of a drug product that is in late-stage (phase 3)trials.The drug is subject to collaboration between Pfizer,the company that originally devel-oped ertugliflozin,and Merck,which presumably reflects the value of the drug candidate.
A pharmaceutical cocrystal approved by the FDA:Entresto t Thus far there are a limited number of pharmaceutical cocrystals approved by the FDA as drug products.Earlier in 2015,Novartis gained approval for Entresto t to treat chronic heart failure.152There are two ionised drug molecules in Entresto t ,in which the drug substance is an ICC comprised of monosodium sacubitril,disodium valsartan and water (CSD Refcode:NAQLAU).153Indeed,there have been other examples of cocrystals reported in the literature where the two components are drug molecules or ions,i.e.drug–drug cocrystals.154Entresto t has proven to be a treatment with a significant mortality benefit and has patient tolerance similar to enalapril.That there are demonstrated outcome metrics for this compound speaks to a significant database of clinical experience in patients with this cocrystal.Pending further approvals from regulatory authorities,Entresto t has a potential market value of several billion USD.This recent approval of a pharmaceutical cocrystal,occurring after the FDA
guidance and EMA reflection paper,may spur increased interest from the pharmaceutical industry in cocrystals as materials for drug products.
Polymorphism in cocrystals
The propensity for polymorphism in cocrystals has and con-tinues to be a subject of interest and debate.That a cocrystal might be less promiscuous with respect to polymorphism and solvates/hydrates than its parent components can be traced back to a case study involving 550crystallization experiments involving carbamazepine and saccharin.114In 2004,an article published by Almarsson and Zaworotko asserted that ‘there may be opportunity to reduce the practical extent of polymorphism of drug compounds specifically by co-crystal formation although there may be exceptions .’1In 2005,the Zaworotko research group further investigated the matter of polymorphism using MCCs derived from components known to be polymorphic (piracetam–gentisic acid and piracetam–p -hydroxybenzoic acid).155There was no evidence of polymorphism in these cocrystals but the authors concluded that ‘the amount of data available concerning the extent of polymorphism in co-crystals remains minimal and that one will not be able to make definitive conclusions even if exhaustive high throughput screenings are conducted.’In a recent review published by Aitipamula et al.156it was reported that only 114polymorphic cocrystals were then known from amongst the thousands of cocrystals archived in the CSD.However,that these studies did not necessarily focus,if at all,upon polymorphism in cocrystals,means that such data cannot lead to general conclu-sions.An even more recent CSD analysis led the authors to conclude that ‘cocrystals were found to be just as likely of being polymorphic as single component systems ’.157The latter is consistent with the posi-tion we took in a 2010review article that presented case studies of polymorphism in cocrystals;‘there remains a dearth of systematic structure and property information on cocrystals.However,at this point there is no reason to believe that pharmaceutical cocrystals will be more or less promiscuous than single component APIs when it comes to crystal form diversity.’158Whereas this is likely to remain the situation in general,it does not preclude the probability that highly pro-miscuous APIs will form specific cocrystals that are robust and parsimonious with respect to polymorphism.
Conclusions
After a decade of progress we return to reflect upon the question posed by Almarsson and Zaworotko in their review on pharmaceutical cocrystals:‘Do pharmaceutical co-crystals represent a new path to improved medicines?’It seems clear that significant progress has been made in all of stages of drug development (Scheme 4).In particular,pharmaceutical cocrystals can modulate important PK parameters such as T max ,C max and AUC for APIs with poor solubility and they therefore o?er an innovative approach to improve bioavailability.Pharmaceutical cocrystals can also be considered novel,non-obvious and of utility and as such they can be protected by composition of matter patents.Regulatory bodies have also recognized the potential
of
Fig.11The structure of the MCC ertugliflozin:L -pyroglutamic acid.The cif file was created from published fractional coordinates and unit cell parameters.151a
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cocrystals by publishing guidelines for industry.In short,after 10years of discovery and development of pharmaceutical cocrystals,many reported improvements in preclinical performance,regulatory attention and intellectual property protection,the answer is a qualified ‘yes’.Further,ICCs have recently emerged and o?er even greater diversity of composition to modulate physicochemical properties.This is because they are necessarily comprised of at least three components,meaning that two of them can be varied.
Challenges remain
Large-scale synthesis and stability in the presence of excipients are,as with any type of crystal form,unpredictable and must be addressed.Further,diversity is a double-edged sword,since the discovery of hundreds of cocrystals requires time for discovery,property evaluation and selection.Time is a precious and often limiting commodity in pharmaceutical development.It is pre-sumed that,as more drug products based on and enabled by cocrystals are introduced,pharmaceutical cocrystals will gain widespread acceptance and secure an even firmer foothold in drug development.
Acknowledgements
We gratefully acknowledge the support of Science Foundation Ireland for Award 13/RP/B2549.
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