OUTSOURCING


some extent from pKa data, cocrystals are not. Formation can be inferred from known functional group interactions, such as Etter’s rules,4 but these predictions are only successful in an estimated 30 per cent of cases.5 Even when observed, the properties of the resulting cocrystal can elude prediction. For example, in our recent study on five structurally related non-steroidal anti- inflammatory drugs (NSAIDs),6 four formed cocrystals with nicotinamide (example in Figure 1), but the solubility and stability of the resulting cocrystals were remarkably different. As with salts, the challenge is not so much in finding cocrystals, but development of an operable scale-up method. Control of purity and particle size usually requires a solution- based method, for which knowledge of ternary phase diagrams and in situ crystallisation development tools, such as FBRM and PVM (Fig 2) become invaluable in this regard.


Although most commonly employed for modifying aqueous solubility, salts and cocrystals modify a range of other properties, such as hygroscopicity, chemical stability, dissolution rate, crystallinity and physical stability, making them an attractive means of generating intellectual property.


Amorphous phases


It is worth noting that the level of solubility enhancement through the use of crystalline salt and cocrystal forms may not be sufficient for large insoluble and/or lipophilic (also known as ‘brick dust’ and ‘grease ball’) molecules. In such cases, amorphous phases may be more advantageous. The solubility enhancement possible with amorphous material has been reported as 10 to more than 1000 times greater than crystalline forms in some cases,7 with 2- to 10-fold increases much more common in practice. However, as they are inherently more chemically and physically unstable than crystalline forms, amorphous formulations require increased investment to develop and stabilise. As a result of this need for stabilisation with excipients, amorphous dispersions are traditionally the reserve of formulation specialists in late-phase development. However, this huge solubility enhancement can also be used to great benefit during preclinical studies. Due to the improvements in targeted drug therapies, it is becoming increasingly difficult to demonstrate a toxic effect during ascending-dose animal studies. This requires higher dosing and bioavailability quickly becomes solubility-limited due to the increasingly lipophilic character of new chemical entities. In many cases for salts, cocrystals and amorphous formulations, the


solubility enhancement is short-lived ‘kinetic’ solubility, before a more stable, less soluble form precipitates in vivo. The challenge to formulators is to sustain the enhancement long enough to maximise bioavailability.


Screening platform for amorphous solid dispersions


Almac have developed a screening platform for amorphous solid dispersions, formufastTM SD, which assesses the interaction of stabilising polymer and API in the solution state. Stronger interactions have been linked with stability in the solid dispersion,8 and precipitation inhibition.9 Variations on this platform have also been successfully employed for screening excipients for oral and intravenous formulations, formufast™ PO & IV, to provide a scientific rational approach to early-phase formulation development. The historical approach was stepwise, with simple formulations incrementally changed until a ‘hit’ was achieved, much in the same way as with salt screening, as discussed earlier. This methodology is more likely to miss the best possible formulation and does not generate the deep understanding that can streamline later-phase (clinical) formulation development, leading to calls for a more systematic approach.10


The formufast oral and IV screens are a rapid, low-cost means of systematically assessing many excipients, as combinations in different proportions or by varying the order of addition. From these small-scale tests, a rational design for preclinical formulation can be identified from kinetic solubility and precipitation inhibition in aqueous media or lipidic vehicles.


Of course, there are always difficult APIs that may not form stable amorphous dispersions, or where enhancement from salts/cocrystals is still inadequate. Since poor solubility also imparts a poor dissolution rate, this implies that the bioavailability of some APIs is reduced merely because they are not dissolving fast enough in vivo. The simplest way to increase the rate is by increasing surface area through particle size reduction. The micronisation of drugs is now commonplace, with jet milling and spray drying routinely carried out at manufacturers such as Almac. Micronisation increases dissolution rate but tends not to influence the equilibrium solubility of a drug,11 except by disordering the crystallinity of the particle surface. Since surfaces have a higher free energy (and higher solubility) compared to the bulk, particles have to be sub-micron in size before this phenomenon can be exploited. This has led to the rise of nanosuspensions


Fig 2: In situ PVM (particle vision & measurement) image of a crystal suspension.


for drug delivery in the past two decades.12 These sub-micron colloidal dispersions of drug particles are stabilised by surfactants and enable increased bioavailability, such as the 16-fold increase reported for Danazol.13 Some preparation techniques remain under patent protection, such is the level of commercial interest. However, research samples can be successfully scaled down and tested,14 prior to committing to these technologies at full scale.


In summary


As an integrated service provider, Almac can employ the full arsenal of solubility enhancement tools and brings a wealth of experience in synthetic chemistry, solid-state services and formulation to provide clients with workable cost-effective solutions, and allow the best candidates to progress into the clinical phase rapidly and with minimal spend. Almac’s Physical Sciences group offers the complete range of screening, development, analytical and legal support services relating to solid forms in drug substance and drug product, uniting the company’s expertise in process chemistry, operations and formulation to provide an integrated, synergistic solution to our clients’ needs.


For further information and references contact the author: Dr Noel Hamill Investigator - Physical Sciences API Services & Chemical Development Almac 22 Seagoe Industrial Estate Craigavon BT63 5QD, United Kingdom Tel: +44 28 3833 2200 Fax: +44 28 3833 2299 Email: pharmaservices@almacgroup.com Web: www.almacgroup.com


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