Key strategies central to overcoming poor API solubility - Almac

OUTSOURCINGKey strategies central toovercoming poor API solubilityNoel Hamill, an investigator with the Physical Sciences Group at Almac, discusses variousfit-for-purpose and cost-effective routes to enable rapid progression of new drugs intoclinical development.The number of novel drug candidateswith solubility-limited bioavailability isincreasing and this presents anindustry-wide challenge to effective andefficient drug development. The widespreaduse of high throughput screening in drugdiscovery and the tendency towards targetswith more lipophilic binding sites are factorsthat have contributed significantly to poorsolubility of new active pharmaceuticalingredients (APIs). 1 Rather than seeking are-design of the molecule through themedicinal chemistry route, solid-statechemistry and preformulation development area fit-for-purpose and cost-effective means ofenabling rapid progression into the clinicalphases.Improving drug solubilityTo date, the most common means ofimproving drug solubility has been saltformation, with around half of all drugs in theFDA Orange Book marketed as salts. 2 Saltscan increase solubility by several orders ofmagnitude compared to the un-ionised API,albeit over a specific pH range. Although saltscreening is recognised as an essential part of24sp 2 Inter-Active September/October 2012drug development, it is often restricted to alower-priority activity for the medicinal chemist,development chemist or formulator toaccomplish alongside other tasks. For thosewho have not had experience in this area,screening can be narrow in scope and ‘riskaverse’, with the first crystalline ‘hits’ generallyaccepted as a successful outcome. Forexample, hydrochloride is not automaticallythe best choice for a basic molecule, as thedissolution rate and bioavailability may beretarded as a result of the common ion effect.Restricting the screening to ions that havebeen previously used in marketed drugs doesnot necessarily mitigate risk either; justbecause hydrobromic acid andethylenediamine were (and are) readily used inorganic chemistry labs does not mean thatthey would be acceptable to today’sregulators.It is true that while the methodology for saltscreening is not difficult, the understanding ofsalt formation, toxicology and solid-statecharacterisation is essential to create the bestopportunity for drug improvement and avoidincorrect (or costly) selection of the ‘wrong’form of an API. To this end, a tailored scientificFig 1. The formation of cocrystals: flufenamic acid/nicotinamide cocrystal structure.investigation is preferable to a generic highthroughput experimental screen, as severaliterations with different conditions may benecessary to coax the first good-qualitycrystals to nucleate.Changing the salt form during the clinicalphase of a drug should be avoided becausethis is regarded as a change in the drugsubstance from a regulatory point of view,which results in costly repeated toxicological(‘tox’) bridging studies. This implies that mosteffort on salt formation is applied during thesynthesis of the preclinical ‘tox’ batch. Forsmall and virtual pharma and biotechcompanies, using an integrated supplier likeAlmac for project management of synthesis,screening, form selection and ‘tox’ studies inparallel (known as rapidd) can reduce riskand minimise spend by eliminating theextended time and loss of information fromtechnology transfer.The main drawback with salts is that, bynecessity, the API must be an acid or base ofsufficient strength to enable a stable salt toform and, therefore, for a weak acid or base,only a few non-toxic, pharmaceuticallyacceptable counter-ions may be available forscreening. This is not the case for cocrystals,which are stoichiometric mixtures heldtogether by hydrogen bonds, as there is norequirement for ionisable moieties and allowsa much wider range of excipients to bescreened. Although known about for a longtime as ‘molecular complexes’ or ‘additioncompounds’, cocrystals have only recentlyattracted attention as a tool for rescuinginsoluble drug candidates from rejection.As the drug is not ionised, there is anenhancement in the ‘kinetic’ solubility, not afundamental change in the thermodynamicequilibrium solubility afforded by salts atcertain pH. Nonetheless, the solubilityadvantage can be substantial, with up to a150-fold increase reported for carbamazepinecocrystals. 3Whereas salt formation is predictable to

OUTSOURCINGsome extent from pKa data, cocrystals arenot. Formation can be inferred from knownfunctional group interactions, such as Etter’srules, 4 but these predictions are onlysuccessful in an estimated 30 per cent ofcases. 5 Even when observed, the propertiesof the resulting cocrystal can elude prediction.For example, in our recent study on fivestructurally related non-steroidal antiinflammatorydrugs (NSAIDs), 6 four formedcocrystals with nicotinamide (example inFigure 1), but the solubility and stability of theresulting cocrystals were remarkably different.As with salts, the challenge is not so much infinding cocrystals, but development of anoperable scale-up method. Control of purityand particle size usually requires a solutionbasedmethod, for which knowledge ofternary phase diagrams and in situcrystallisation development tools, such asFBRM and PVM (Fig 2) become invaluable inthis regard.Although most commonly employed formodifying aqueous solubility, salts andcocrystals modify a range of other properties,such as hygroscopicity, chemical stability,dissolution rate, crystallinity and physicalstability, making them an attractive means ofgenerating intellectual property.Amorphous phasesIt is worth noting that the level of solubilityenhancement through the use of crystallinesalt and cocrystal forms may not be sufficientfor large insoluble and/or lipophilic (alsoknown as ‘brick dust’ and ‘grease ball’)molecules. In such cases, amorphous phasesmay be more advantageous. The solubilityenhancement possible with amorphousmaterial has been reported as 10 to morethan 1000 times greater than crystalline formsin some cases, 7 with 2- to 10-fold increasesmuch more common in practice. However, asthey are inherently more chemically andphysically unstable than crystalline forms,amorphous formulations require increasedinvestment to develop and stabilise. As aresult of this need for stabilisation withexcipients, amorphous dispersions aretraditionally the reserve of formulationspecialists in late-phase development.However, this huge solubility enhancementcan also be used to great benefit duringpreclinical studies. Due to the improvementsin targeted drug therapies, it is becomingincreasingly difficult to demonstrate a toxiceffect during ascending-dose animal studies.This requires higher dosing and bioavailabilityquickly becomes solubility-limited due to theincreasingly lipophilic character of newchemical entities. In many cases for salts,cocrystals and amorphous formulations, thesolubility enhancement is short-lived ‘kinetic’solubility, before a more stable, less solubleform precipitates in vivo. The challenge toformulators is to sustain the enhancementlong enough to maximise bioavailability.Screening platform for amorphoussolid dispersionsAlmac have developed a screening platformfor amorphous solid dispersions, formufastTMSD, which assesses the interaction ofstabilising polymer and API in the solutionstate. Stronger interactions have been linkedwith stability in the solid dispersion, 8 andprecipitation inhibition. 9 Variations on thisplatform have also been successfullyemployed for screening excipients for oraland intravenous formulations, formufastPO & IV, to provide a scientific rationalapproach to early-phase formulationdevelopment. The historical approach wasstepwise, with simple formulationsincrementally changed until a ‘hit’ wasachieved, much in the same way as with saltscreening, as discussed earlier. Thismethodology is more likely to miss the bestpossible formulation and does not generatethe deep understanding that can streamlinelater-phase (clinical) formulation development,leading to calls for a more systematicapproach. 10The formufast oral and IV screens are arapid, low-cost means of systematicallyassessing many excipients, as combinationsin different proportions or by varying the orderof addition. From these small-scale tests, arational design for preclinical formulation canbe identified from kinetic solubility andprecipitation inhibition in aqueous media orlipidic vehicles.Of course, there are always difficult APIs thatmay not form stable amorphous dispersions,or where enhancement from salts/cocrystalsis still inadequate. Since poor solubility alsoimparts a poor dissolution rate, this impliesthat the bioavailability of some APIs isreduced merely because they are notdissolving fast enough in vivo. The simplestway to increase the rate is by increasingsurface area through particle size reduction.The micronisation of drugs is nowcommonplace, with jet milling and spraydrying routinely carried out at manufacturerssuch as Almac. Micronisation increasesdissolution rate but tends not to influence theequilibrium solubility of a drug, 11 except bydisordering the crystallinity of the particlesurface. Since surfaces have a higher freeenergy (and higher solubility) compared to thebulk, particles have to be sub-micron in sizebefore this phenomenon can be exploited.This has led to the rise of nanosuspensionsFig 2: In situ PVM (particle vision &measurement) image of a crystal suspension.for drug delivery in the past two decades. 12These sub-micron colloidal dispersions ofdrug particles are stabilised by surfactantsand enable increased bioavailability, such asthe 16-fold increase reported for Danazol. 13Some preparation techniques remain underpatent protection, such is the level ofcommercial interest. However, researchsamples can be successfully scaled downand tested,14 prior to committing to thesetechnologies at full scale.In summaryAs an integrated service provider, Almac canemploy the full arsenal of solubilityenhancement tools and brings a wealth ofexperience in synthetic chemistry, solid-stateservices and formulation to provide clientswith workable cost-effective solutions, andallow the best candidates to progress into theclinical phase rapidly and with minimal spend.Almac’s Physical Sciences group offers thecomplete range of screening, development,analytical and legal support services relatingto solid forms in drug substance and drugproduct, uniting the company’s expertise inprocess chemistry, operations and formulationto provide an integrated, synergistic solutionto our clients’ needs.For further information andreferences contact the author:Dr Noel HamillInvestigator - Physical SciencesAPI Services & Chemical DevelopmentAlmac20 Seagoe Industrial EstateCraigavon BT63 5QD, United KingdomTel: +44 28 3833 2200Fax: +44 28 3833 2299Email: pharmaservices@almacgroup.comWeb: www.almacgroup.comSeptember/October 2012 sp 2 Inter-Active25