Solid form: Why is it important to consider in API development?

06th Jul 2021

In this webinar, our experts will discuss our solid form capabilities and the importance of these in API development.

[Charlotte Chapman]: Before I hand over to the solid form team, I’d like to do a quick introduction to Sterling. Sterling is a contract development and manufacturing organisation, with sites in the UK, US and Ireland. Sterling’s mission is to be the preferred partner for the pharmaceutical industry. We have expertise and capabilities to take your product from discovery through to commercial launch. From grams to tons, we have the knowledge and the capacity to take your product through the entire lifecycle. Now I’ll hand over to Jamie, John and Andrew for the webinar.

[John Mykytiuk]: Hello everyone, I’m John Mykytiuk, the Solid State Manager here at Sterling. Using my experience, I will ensure that we have a clear understanding of your requirements and can assist in achieving them. As a part of Sterling’s ongoing expansion, the new Material Science Centre at our Dudley headquarters houses our milling and micronisation suites, with containment down to OEB4 class materials. We have scale up a commercial mills so that we can conduct appropriate scale up. The Material Science Centre is also home to the solid form development team, complementing API development and allowing us to provide solid form development as a new offering of our first class services to our clients.

Our solid state chemistry team are able to provide a range of services including salt or co-crystal screens, polymorph screens, pre-formulation evaluation, and crystallisation development. But why is appropriate solid form development necessary? First, we need to understand the relevance of salt or co-crystal formation and polymorphism of an API, and then the subsequent development of a crystallisation process to afford the target API version. We will then briefly cover the various aspects of solid form development and manipulation that Sterling can offer, detailing some of the instruments we employ before closing this presentation with a scenario outlining a complete solid form development program for an API.

[John Mykytiuk]: The differences in the packing arrangements of the same API molecule can give rise to differences in the physical properties and chemical processes of the API. This is known as polymorphism.

The packing arrangement of the same API molecule can be further modified by salt or co-crystal formation as well as hydrate or solvate formation, which will also modify the physical behaviour of the API. These differences in API physical properties can alter the bioavailability. For instance, one version of the API may be more active than another. If the API version is not protected correctly by intellectual property, the API might be open to exploitation by the competition.

The European Medicines Agency classifies an API solid in terms of its appearance, which is particle shape, and the internal structure. The most relative arrangements of the internal structure of an API we need to consider are amorphous, the most disorganised, and crystalline ordered, and how the various compositions might be obtained for crystalline solids. For instance, the external appearance, that is particle shape, can influence the isolation of the API and the bulk powder properties, while an amorphous solid which would have the high solubility might have a poor shelf life. Alternatively, we might have a crystalline solid with a low melting point that is not suitable for down-stream processing. An alternative arrangement of the API might offer a different polymorph or version such as assault or hydrate, which could improve these characteristics and subsequent processing.

A solid API can be classed by the following five property characteristics: thermodynamic packing, kinetic surface, and mechanical. Within these characteristics the main parameters which can influence the solid state behaviour of an API are solubility, dissolution rate, stability, high gross capacity, particle size, habit and compatibility. By gaining an understanding of these parameters they can be used to guide the solid form development of an API.

Also, the biopharmaceutical classification of an API, particularly at the discovery stage, can highlight potential challenges an API might present for oral administration. Many new chemical entities fall into classes II and IV of this classification. With class II APIs, an improvement of API solubility would be expected to improve efficacy. The most challenging APIs are those that fall into class IV since they are also poorly absorbed. A low therapeutic dose for efficacy that is high activity is desirable to enable the modification of the API solid state to have a potentially desirable effect such as particle size or an amorphous API dispersion.

Appropriate screening will aid in selecting the most suitable version of an API to progress forward to crystallisation development. But why do we need to highlight crystallisation?

The final operation in the production of an API solid is crystallisation which defines all the attributes of the API. But we also can use crystallisation for the isolation of intermediates. Crystallisations can be problematic since there are many competing characteristics of the material that need to be addressed during this operation. These include target chemical purity, which is typically very pure, crystallisation yield, isolated API form or version, and solid morphology, that is particle habit and particle size. These characteristics can impact further upon unit operations, from the rate of filtration and drying of the isolated solid, secondary processing such as particle size reduction, and drug product manufacture.

A controlled crystallisation process will reproducibly afford the same quality of material that should behave the same with regards to physical chemical properties, hence the need for crystallisation development.

A thorough crystallisation development program requires an understanding and appreciation of four interconnected aspects. It is necessary to understand crystal basics. At the point of crystallisation, what is the rate of nucleation and the subsequent mechanism and rate of crystal growth? What is the maximum extent of crystallisation that can be achieved and subsequent yield of the API from a chosen solvent? This connects with the assessment of process variables such as the solubility of an API in a range of solvents or solvent/anti-solvent mixtures over a given temperature range. What is the metastable zone width of the API in the given solvent system and what cooling rate, if applicable, affords controlled crystal growth from a suitably developed seed bed?

Both the crystal basics and process variables are underpinned by the required material attributes. Will the crystallisation process afford the desired API version with the target particle size and suitable chemical purity. At the heart of all crystallisation development is the necessity to afford a crystallisation process that is economically viable upon scale up. The cost of running a process should be no greater than necessary and the safest without reducing material quality. For example, if both an ICH class III and class II solvent afford the target API version, the class III solvent would be preferred. Consideration of the API isolation, that is filtration and drying behaviour, should not be neglected and not require an unnecessarily long time. A poorly developed crystallisation could afford a suspension consisting of small crystals. This could result in poor separation of solids and solvent mixtures to slow filtration and drying operations, which could demonstrate poor flow ability and is generally bad news for production. Ideally, large crystals are desirable as they typically result in fast filtration, are easy to dry, can demonstrate better solid flow ability for bulk particle manipulation, formulation or drug product manufacture, and are generally good news for production. A poorly developed crystallisation runs the risk of poor reproducibility with lot to lot variation as the process is out of control. This can have a negative effect upon downstream processes with potential impact upon the formulated drug product. Effective crystallisation development is a combination of understanding both science, that is solvent properties, molecular behaviour, crystallisation process, and engineering principles and measurement, which all underpin the control of material attributes.

For an API, solid-state science can span from IND to phase III clinical in the life cycle of API development, as well as next generation development. Solid form development operations can be closely connected especially early during API development with salt and polymorph screens and pre-formulation evaluations implemented to ensure that the most suitable API version is selected for further development. Alternatively, a client may already have chosen their target API version, in which case crystallisation development would be required.

Here, we see the various solid state elements and their interconnectivity which are offered to our clients by Sterling. The outcome is an API or substance with the required attributes, that is purity, form or version, composition, particle habit, and particle size distribution. Each element can be a standalone activity, but they bridge API synthesis to formulation development and drug product manufacture.

And now I will hand you over to Jamie, another member of the solid form team, who will describe the various solid state elements we can offer in more detail.

[Jamie Marshall]: Hi, I’m Jamie Marshall and I support the solid form development of compounds and APIs for Sterling’s new, and existing, solid form development projects.

Where an API demonstrates appropriate characteristics, a salt or cocrystal screen can be considered as a course for altering the properties of an API without changing the pharmacologically active molality. There are a number of key properties that can be modified, and potentially improved, by generating a salt or cocrystal version of an API/ These include solubility, which can have an influence upon bioavailability, although the solubility of different salts of an API might vary significantly with different counter ions. The dissolution profile may vary with different salts or cocrystals. Physical chemical properties and the manufacturability of the API version, such as thermal characteristics including melting point, hygroscopicity, particle size, propensity to polymorphism, and overall chemical stability, can vary significantly between the free API and different API salt or cocrystal versions. For example, where crystallisation of the free API alone may fail to sufficiently improve chemical purity, implementing a salt or cocrystal formation could provide an opportunity for impurity control. The regulatory position of pharmaceutical cocrystals has been clarified by the FDA as distinguishable from salts, with the API and co-former coexisting in a unit cell lattice with a defined stoichiometry and interacting non-ionically. The European Medicines Agency distinguished cocrystals as binary adducts in their classification of API solid-state materials. Appropriate investigations will aid in identifying the most suitable API versions ahead of further development, with potentially multiple salt candidates compared and assessed. However a salt screen isn’t just useful for early phase development or to potentially identify an impurity controlling salt formation, a broad salt screen assessing a significant range of counter ions or core formers and solvent mixtures can be utilised to generate intellectual property for API versions.

Whether we are investigating an API salt version or the free API, it is necessary to perform polymorphism investigations to assess the propensity of an API to polymorphism and begin to understand the polymorph landscape, as it is also a regulatory requirement. As with the salt screen investigation, a number of key parameters can be modified and potentially improved by generating and isolating a specific polymorphic form or version of an API. The API efficacy and both chemical and form stability can vary depending upon the physical structure of the API. Identifying a suitable crystallisation that affords a given API version could provide an opportunity for impurity control. By understanding the physical properties of a range of potential solid form candidates we can understand the relationship between different forms to establish a form hierarchy. We can then recommend the ideal API version candidate to progress and succeed through API manufacture and subsequent drug product manufacture with required efficacy and stability. The extent of investigation performed to understand the polymorphic landscape of an API, is governed by a balance between the cost of development and the risk of selecting what turns out to be an unsuitable solid form forth of the development. An expanded polymorphism investigation utilising a broad range of solvents, solvent mixtures, and methods of manipulation, can be implemented to generate intellectual property for API versions. As a general rule, the more time you spend looking for new polymorphs or versions, the more likely you are to uncover them, even if they are nation from very specific conditions.

The act of a salt screen where appropriate and a polymorphism investigation may afford a number of potential solid form candidates. In order to aid suitable solid form selection we can consider a number of assessments that fall under the umbrella of pre-formulation evaluation. Solubility and stability determination of the API version candidates in biorelevant and aqueous buffers can identify the API version with the most appropriate aqueous solubility, if a target requirement, and identify any instances of solid form or chemical instability under the given conditions, both of which are inappropriate for solid form development. Conditional storage of API version candidates under accelerated stability conditions may be utilised to assess form and chemical stability to temperature alone and to both temperature and humidity. Any instances of instability are a concern or could at least highlight potential necessity for additional controls during drug product manufacture. The API version candidates may also be subject to compression and manual particle attrition to simulate conditions that could be applied during milling of an API or drug product manufacture. Candidates that demonstrate instability to compression force or the mechanical particle attrition may be considered less robust than other candidates. Preformulation evaluation is not strictly a standalone activity from salt screens or polymorph screens, aspects of it may be implemented during screens where appropriate. Alternatively, the screening investigations may only identify one suitable solid form candidate, thus rendering pre-formulation evaluations unnecessary.

The goal of effective crystallisation development is to generate the target API version of required chemical purity, and particle characteristics, with suitable recovery for drug product manufacture. A bottom-up operation, the crystallisation process is used to control impurity levels, ensure the target API version is generated, and afford a reproducible particle habit and size distribution. A controlled crystallisation process is governed by crystal growth which is a function of the API solution saturation, which itself will be affected by temperature or solvent mixture composition, and seeding with the API target version.

Whilst an ideal crystallisation process would afford the required API version with a suitable particle size distribution direct to manufacture, sometimes the physical modification of bulk API version particle properties is employed to improve drug product manufacture or enhance the API performance in terms of dissolution characteristics. Bulk particle manipulation is not strictly essential as target particle size may not be dependent upon the method of administration. Where it is required though, termed a top down operation, milling and micronisation operations can be applied to modify API version particle properties which may be significant, such as particle shape, particle size, particle size distribution, hygroscopicity, adhesiveness, density, flow ability, wettability, and compaction, all of which are important for drug product manufacture and, in turn, efficacy. We have reviewed why appropriate solid form development is important to ensure the most suitable API version is identified and pursued, but physically how do we characterise an API what properties do we consider and how do we examine them when it comes to solid form analysis? In solid form characterisation multiple instruments can be utilised to assess the various properties.

First and foremost is API version determination, which API polymorphic form, salt, co-crystal, solvent or hydrate have we isolated? X-ray powder diffraction is the main workhorse in rapid API version determination, generating an x-ray diffraction pattern that is unique to each API version. Though it should be stressed that XRPD data alone is not enough to identify the nature of a sample, only to confirm that the crystal lattice either matches existing references or affords a different diffraction pattern. To support API version determination, thermal characterisation by differential scanning calorimetry and thermal gravimetric analysis can be employed to reveal thermal features unique to each API version similar to XRPD data. The thermal events can identify an API version’s melting point, the presence of additional thermal events, potentially indicative of mixed versions or an anti-tropism, determine the onset of decomposition, and potentially differentiate between channel and stoichiometric solvates and hydrates.

Ion chromatography, NMR spectroscopy, and Karl Fisher titration may be employed to determine whether an API version is a salt, cocrystal, solvate, or hydrate, which also falls into the realm of composition determination, along with gas chromatography, to estimate the solvent content in a material. Fourier transform infrared spectroscopy may be utilised to differentiate between a salt and a cocrystal though raman and solid-state NMR spectroscopy that are available via outsourcing could also be employed. Another aspect of API version composition to assess is the impurity profile determined by HPLC. The impact of impurities upon a crystallisation or salt formation can be significant hence the requirement to understand the impurity profile composition of the API. To further support the understanding of the thermal features complementary to DSC and TGA is hot stage microscopy. Hot stage microscopy enables us to visually observe what happens to the sample as it is heated up, allowing us to attribute events observing the DSC thermograph to visual changes observed of the microscope. We can also perform thermal manipulations, heating the API version to a temperature of interest as determined by the thermal profile and then cooling again, before examining the thermally manipulated solid by XRPD to assess the potential version change. Variable temperature XRPD, available via outsourcing, could also be employed to get a more thorough understanding of API version behaviour across a range of temperatures. Particle habit and particle size determination can both be determined qualitatively by optical microscopy and used to corroborate formal particle size distribution examination by laser light scattering.

The hygroscopicity of a solid that is the ability of an API version to take up water can be assessed by dynamic vape absorption to assess the extent of water uptake and loss with varying humidity. The solid isolated following storage at either extreme of humidity can be examined by XRPD to assess for potential version change, such as affording an anhydrous version or a hydrate. Variable humidity XRPD, again available via outsourcing, could be employed to examine version change by XRPD across a range of humidity. Th e solubility of an API version in a given medium is most commonly assessed via HPLC. This is useful for measuring the solubility profile of an API version determining the meta-stable zone width, that is the solubility range between the API solution entering saturation, the point at which crystallisation can occur, to supersaturation, where crystallisation is spontaneous and uncontrolled can be challenging. However, equipment does exist that can determine the solubility profiles and metastable zone width of an API version under given conditions via turbidity. Finally, API version stability can be assessed by both HPLC and NMR, to assess chemical instability, and by DSC to assess potential solid form version instability to a high degree of sensitivity. Appropriate DSC method development can reveal mixed version impurities at less than 0.001% impurity content.

We’ve covered why appropriate solid form API development is important and how we can characterise various API versions. Now I shall hand you over to Andrew, another member of the solid form development team, who shall describe a scenario of an API that has been taken through the various solid state elements, highlighting how potential API version candidates are taken through and assessed in this process.

[Andrew Blyth-Dickens]: Hi, my name is Andrew Blyth-Dickens. I’m a member of the solid form development team here at Sterling. Today, as part of this webinar, I will take you through a possible scenario that could be encountered during development of an active pharmaceutical ingredient.

An API was presented for development, clinical manufacture, and progression in the formulation and drug product manufacture as a controlled solid phase. Based on the chemicals structure, it was assumed that the free API would have limited aqueous solubility and so a salt screen investigation was conducted to identify a suitable salt version, or versions, with enhanced solubility and, in turn, improved bioavailability. Given the structure of the API, the estimated PKA for the protonation centres was low, therefore only strong acidic counter ions were considered likely to form suitable salts of the API. As common salt screen practice dictates, qualitative or visual solubility determination of the free API in a range of solvent and solvent mixtures indicated four solvent systems to be more suitable for salt formation investigations. Of the 15 camera ions assessed across the four solvent or solvent mixtures, 12 mobile suspensions, termed hits, were forded. Of those 12 hits, only four were considered to demonstrate desirable physico chemical and solubility characteristics.

The table shown summarises the characteristics of the four key API salt hits. Both the counter ion A and C salts demonstrated form consistency by XRPD and DSC, and were reproducible from multiple crystallisation solvent mixtures. But their aqueous solubility was relatively low compared to the counter ion B and D salts. The downside of the latter salt versions were potential issues of solvent formation and evidence of form stroke version variability. The aqueous solubility of the free API was non-existent in water as anticipated, so any API solubility as a salt was an improvement over the free API. The remaining eight hits demonstrated physical issues ranging from poor aqueous solubility, complex DSC firmographs, significant evidence of solvation and potential thermal instability of the salts. The fact that different salt versions were isolated and characterised is still useful from an intellectual property perspective and with further screening variation such as different API dissolution solvents, more alternative desirable versions might have been identified.

To aid salt version selection, the four API salts identified were carried forward into a pre-formulation evaluation in order to discriminate and identify the preferred salt of the API based upon solubility and accelerated stability assessments. To support these evaluations, further quantities of the salts were required. The counter ion B and C salts were successfully isolated as the target di-salts upon scale up. The counter ion A salt was interestingly also isolated as a di-salt upon scale, despite being isolated as a mono-salt during the initial screening investigations. However, on two occasions the count ion D salt was isolated with varying API to counter ion ratios and with significant residual solvent content and was consequently removed from further evaluations. With the number of API salt versions reduced to three, the free API and salt versions were assessed for their solubility and form behavioUr in various dissolution media at 37 degrees centigrade. Form and chemical stability were also assessed following three weeks of conditional storage and accelerated stability conditions.

Here we see a table detailing the API and API salt version solubility in the various aqueous and bio-relevant media and the measured pH of the mixtures. It is quite complex at first glance, but we’ll highlight the key observations of note. The solubility and pH characteristics of the counter ion A and B salts were similar across the range of dissolution media examined, with solubility greater than 30 mg/ml in all media besides the pH 4.5 acetate buffer or ph 5 FeSSIF by irrelevant media. The free API was much less soluble than both salts, except in 0.1 molar hydrochloric acid and the acetate pH 4.5 buffer, where the solubilities compared to the salts were similar. The HCL buffer demonstrated a near 30 mg/ml solubility on the acetate of A demonstrating almost non-existent solubility.

The solubility and pH characteristics of the count ion C salt lays somewhere between those of the other two salt versions and the free API. XRPD patterns of all the isolated solids from the equilibrations of the free API, counter ion A and counter ion B salts, all match the free API indicating disproportionation of the salts back to the free API as a solid, and leaving the count ion dissolved in solution as suggested by the pH measurements. In contrast, the XRPD patterns of all the isolated solids from the equilibrations of the counter ion C salt matched the input salt suggesting salt stability.

The detailed table shown here is a summary of the solid form characteristics of the API salt versions isolated, including the impact of humidity by DVS, and humidity and temperature following conditional storage. The salt formation of the counter ion B and C salts afforded significant improvements to the overall chemical purity compared to the input free API, whilst the formation of the count iron A salt had relatively little impact on the overall chemical purity. The solid form characteristics of the counter ion B and C salts were reproducible, affording crystalline solids with simple thermal profiles, whilst the counter ion A salt demonstrated partial solvation observed by subtle differences in the XRPD pattern and weight loss by TGA prior decomposition. After three weeks of storage at 40 degrees centigrade and 75 percent relative humidity, there was no evidence of appearance change, chemical degradation, form change or hydration for the free API counter ion B salt or counter ion C salt. However, there was evidence of appearance change and hydration of the counter ion A salt. These observations, the impact of humidity upon the API version with storage, was supported by dynamic vapor sorption findings, where the counter ion B and C salts were free-flowing powders upon isolation and 90% relative humidity, whilst the counter ion A salt demonstrated significant water uptake and afforded a slightly sticky solid and 90% relative humidity. Taking into account the observed propensity dehydration, the API counter ion A salt was deemed unsuitable for further examination.

From the 15 counter ion salt screen afforded four API salt candidates considered suitable for further assessment, only two API salt candidates, the counter ion B and C di-salts, were considered suitable as the most preferred versions to progress into parallel polymorphism investigations. The objectives of the polymorph screen were to assess the propensity of the two salt versions to polymorphism or version change, characterise any new versions and rate their potential for progression to further development on the basis of salt version stability, solubility and particle habit. Parallel polymorph screening of both salts began with a calibration of the supplied crystalline salts in various solvents and solvent mixtures to assess potential form change and visual solubility. Following that, the amorphous version of both salts was generated. It’s important to isolate the amorphous version of an API or API salt as the amorphous version is thermodynamically highly energetic and features no form memory that could influence subsequent equilibrations. After the equilibration screen, dissolution of the API in appropriate solvents at elevated temperature and cooling is representative of cooling crystallisation. Dissolution in solvent and charging appropriate solvents that induce power solubility is representative of an anti-solvent-driven crystallisation. This list of investigations is common in most polymorph investigations and can be expanded in terms of the initial solvent library utilised, the variety and composition of mixed solvent equilibrations, and the crystallisation trials modified that include rapid or slow cooling and controlled or reverse anti-solvent edition to name some of the operations that might induce form change.

Following polymorph screening of both salts, the API counter ion B di-salt demonstrated considerable propensity aversion change, avoiding two polymorphic forms, evidence of solvates, multiple hydrates and multiple anhydrates, as well as evidence of partial salt disproportionation in one solvent. API counter ion C di-salt predominantly afforded one polymorphic form, identified as pattern A. Equilibration of the amorphous salt predominantly returned pattern A, resides in two solvents, where patterns B and C both confirmed as unique polymorphic forms and not solvates were isolated. Thermal manipulation revealed pattern A to be the thermodynamically stable form of the di-salt.

Following three programs of investigation, one API counter ion C di-salt, pattern A, was a single selected version of the API, observed to demonstrate little polymorphic variants, no evidence of solvation or hydration, and feature generally improved solubility over the free API. As such, this version was progressed in a crystallisation development. As we have already indicated the main goal of crystallisation development is to develop the protocol that affords the target API version with suitable recovery control of impurities and desirable particle habit. However, there is still potential for new forms or versions to be isolated during development and any that are produced should be fully characterised. As in the polymorphism investigations, all aspects of solid form development should be considered regardless of how far in the development program an API is. We have seen some APIs afford new polymorphic forms as late as GMP production that have had a significant impact upon the timelines regarding the requirement of the API, and completely changed how the final steps of the process have had to be conducted. The salt formation, up to this point, was a very high volume process isolated from over 50 volumes of a high boiling point solvent that could potentially be difficult to control during drying upon scale up, which was considered to be unsuitable. For the selected preferred API salt, initial investigations focused on assessment of aqueous based recrystallisation of the salt from solvent stroke water mixtures. Firstly assessing a range of water miscible solvents and then assessing different solvent stroke water ratios in preferred mixtures. With a range of suitable solvent stroke water mixtures selected, solubility evaluation was performed to understand the nature of the crystallisation with regards to solubility and subsequent control of the rate of crystallisation. The most promising crystallisation systems were scaled up, assessed further and the isolated solids fully characterised affording the proposed recrystallisation of the API salt. However, instead of generating the salt and recrystallising, it or indeed crystallising a free API and then generating a salt, more efficient process would be a direct reactive salt formation driven crystallisation. An investigation was therefore launched into targeting a one-step isolation of the API salt with desirable properties from crude free API.

During the polymorph screen cooling crystallisation of the API salt afforded the target version, pattern A. However early scale up of the process in the crystallisation development program afforded a new polymorphic form, termed pattern D, this version, like patterns B and C, was also a metastable form and converted a pattern A upon thermal manipulation by DSC and TGA. Findings from the polymorphism screen combined with observations from the chemistry development team favoured aqueous based crystallisation systems that would ideally generate the target API salt form, but also afford a greater extent of impurity control over non-aqueous solvents. Equilibration of the API salt in a range of solvent/water mixtures were assessed with an alcohol/water mixture 901 in particular affording the greatest recovery of over 80%. The alcohol/water solvent mixture was assessed as a reactive salt formation crystallisation and was considered to be suitable in terms of recovery and improved composition of the isolated salt. It is noted that certain counter ion and solvent combinations can later potential genotoxic impurity formation. Investigations into the stressed formation of such highly controlled impurities should be performed to ensure such impurities are not generated, or at least suitably controlled, upon isolation. The initial process featured dissolution of the free API in over 30 volumes of alcohol and dissolution of the counter ion in over three volumes of water respective to the free API input. Further investigations revealed that the free API could be dissolved in considerably less alcohol and the counter ion in considerably less water which somewhat improved the recovery. Following a few iterations, a reactive salt formation was devised that afforded the target API salt version with desirable characteristics including suitable particle size distribution and particle habit for clinical evaluation and an 83% recovery that performed well during GMP manufacture on a four kilogram scale.

For this scenario, we assessed 15 counter ions during a salt screen that afforded 12 hits. Only four of which were initially considered suitable to progress. Pre-formulation evaluation was employed to narrow the salt version selection down to two. The subsequent polymorphism screen revealed one salt candidate to demonstrate little evidence of version change, and the other salt candidate to demonstrate version change, affording a range of polymorphs, hydrates, anhydrates solvents and salt disproportionation. Crystallisation development of the selected salt candidate revealed a new polymorphic form. From these investigations, the crystallisation process was reduced from a high volume, two-step salt formation to a considerably more efficient lower volume, one-step salt formation, that afforded the target API salt version with suitable recovery and purity.

[John Mykytiuk]: Solid form development is an important consideration for the final attributes of the API, impacting bulk particle manipulation and drug product manufacture. Although it can affect many aspects of API synthesis A salt or co-crystal version of the API should demonstrate more desirable properties such as improved solubility, prolonged shelf life, and improved solid form properties compared to the free API as well as intellectual property. An understanding of the polymorphic behaviour of the API is necessary for formulation development, drug product manufacture and intellectual property, but also APIs isolation, the final step of API synthesis. Any process that features a crystallisation isolation may benefit from crystallisation development in order to maximise recovery, improve impurity control at key steps, or even improve process throughput via more efficient filtration and drying operations. A process that suffers from poor reproducibility could be a consequence of the solid form behaviour of the compound under specific conditions. An understanding of these conditions could help engender greater control over the process. Solid form development covers a number of elements which span from API synthesis to drug product development and manufacture. These elements are important considerations for your API and are available at Sterling.

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