API Development Trends: Solid Form Development

Sterling Pharma Solutions’ solid state team explore the importance of considering solid form in active pharmaceutical ingredient (API) development and the benefits of crystallisation from the early stages of a product’s lifecycle. They explore how crystallisation can improve API manufacturing processes, bulk particle manipulation, and milling and micronisation. They finish by outlining a case study, showing how the solid state science elements were utilised in the progression of an API in early development.

Why is it important to consider solid form in API development?

The importance of understanding a molecule’s solid form should not be underestimated. It is essential when developing effective drug development programmes, due to the impact it can have on the efficacy of the final drug product and the way the API is manufactured.

The variation of the arrangement of a molecule in a solid crystal lattice is referred to as polymorphism. These variations in the ‘packing’ of these molecules can afford differences in material behaviour and properties. Without modifying the chemical structure of the molecule, and consequently the pharmacology of an active pharmaceutical ingredient (API), the characteristics of the API can also be modified by producing solvates, hydrates, salts and cocrystals if the chemical structure of the API contains amenable moieties.

For an API in early development, the solubility and bioavailability are parameters that are often a focus of attention. By exploring and discovering how these forms and versions of an API affect these parameters from the solid state perspective, these API parameters can often be improved. Furthermore, the intellectual property of the API, such as the solid forms or versions, can be protected via patent, reducing the opportunity of exploitation by other parties.

The melting point of an API is a property that is often routinely used to characterise a drug substance. Solid state investigators will also consider another thermodynamic value, the enthalpy, which is the energy required to melt the API, as well as physical stability. Properties and characteristics of a drug substance as a solid that are often not considered can include hygroscopicity, density and colour, which can be influenced by particle size and habit, chargeability, filterability, millability and the suitability for particle size reduction. Some or all of these can have an impact upon the efficacy of the API in the drug product.

From a biopharmaceutical perspective of the solid dosage form, form stability and dissolution rate are important kinetic characteristics. These can be related to the particle properties of the API and excipients, which can encompass surface free energies, interfacial tensions and the size of the particles, while mechanical properties such as hardness and compactibility can also have a significant impact on the dissolution properties of the formulated drug product performance.

API solubility and permeability and the effect of solid state characteristics

With the introduction of the Biopharmaceutical Classification System (BCS)1, many marketed drugs are characterised as having poor solubility and fall into BCS II or IV2. An even larger proportion of drug substance molecule candidates in development are also characterised as having poor solubility and are further compromised by poor gastrointestinal absorption3.

The BCS has been built upon with the advent of the Developability Classification System (DCS)4. This moves the dose solubility ratio threshold between class I and III, and class II and IV, to lower values in order for a molecule to be considered as soluble.

The other modification introduced by DCS to BCS is the splitting of BCS II into DCS IIa and IIb. This means BCS II compounds with low solubility and high permeability can be categorised as dissolution rate limiting (DCS IIa) or solubility limiting (DCS IIb), see Figure 1. Class I APIs have preferred solubility and permeability, while class IIa APIs are limited by dissolution rate. This might be improved by particle size reduction or the use of dissolution promoters, but for class IIb APIs, the solubility must be improved. This could be achieved by salt/cocrystal formation or using different forms of the API, such as amorphous or metastable forms. The formulation of class III APIs may often include adsorption enhancers, such as lipid vehicles or low molecular weight PEG to improve permeability. Class IV APIs, are considered the most challenging class, and any and all of the options considered for class IIa, IIb and III APIs might be investigated.

Fig 1: The Developability Classification System. A modification of the Biopharmaceutical Classification System.

How can crystallisation improve my API manufacturing process?

Typically, crystallisation is the last step in the manufacture of an API, no matter the DCS or BCS class. High chemical purity is required, as is confirmation that the correct polymorph or version of the API has been isolated and that the particle attributes, such as a suitable particle shape and size, can be achieved by the crystallisation process. This will ensure suitable downstream processing to the drug product and deliver dosage characteristics for optimal efficacy.

In addition, attributes of a solid API influence the efficiency of synthesis manufacturing operations such as filtration and drying, as well as secondary processing such as milling. Prior to further processing, the correct initial solid form must be achieved. Therefore, it is important that the crystallisation process can be controlled so that a process will reproducibly afford the same desired API with a quality profile to meet specification. The isolated API attributes are paramount for formulation development and further evaluation.

Solid form investigations during early API development

When conducting solid form investigations early in drug substance development, there is a need to balance the cost of development with the risk of progressing what could be an unsuitable version of the drug substance. As illustrated in Figure 2, the various solid state science elements are a pivotal link between API development and manufacture and formulation development and drug product manufacture.

Undertaking solid state investigations during the early phase progression of the drug substance molecule presents an opportunity to save time and expense in the overall API and formulation process. These studies can be instrumental in identifying issues early on that would otherwise need to be resolved later in development. Undertaking API solid state investigations can aid the development and selection of a drug product with improved potential of early in vivo evaluation and ultimately, clinical success, which are often common goals.

Fig 2: API development process showing integrated solid form investigations elements.

An API’s properties may be changed without altering the pharmacologically active moiety by forming a salt of the API, if appropriate, or by producing cocrystal versions. By enhancing the solubility of the drug substance, this can improve the dissolution profile and bioavailability. The selection and development of a salt or cocrystal version of the API can improve chemical stability and can also offer an opportunity for impurity control if structurally suitable. Initial formulation studies can be guided through understanding polymorphism, the relationships between API forms and stability. The selection of an ideal version of the drug substance, be it polymorph, hydrate, salt or cocrystal, can guide the formulation investigations in order to enhance stability and efficacy of the API as the drug product.

Polymorphism investigations

The polymorphic forms of your API can vary characteristics such as efficacy, solubility (which can influence bioavailability), stability and physico-chemical properties (including thermal properties, hygroscopicity, flow, filterability and drying efficiency). To define the solid form version hierarchy, the relationship between the API form, hydrates and solvates must be established. The API solid form version with the most desirable properties can then be selected for progression as a suitable drug substance candidate.

Crystallisation development

The development of an API manufacturing process needs to offer effective and efficient processing, whilst ensuring the drug substance has the characteristics required.  Crystallisation of an API is the process that will reliably produce the solid state, regardless of the polymorphic form of the drug substance or the version of the API as a hydrate, salt or cocrystal; it is a ‘bottom up’ operation. It can also control the impurity levels present and the particle size distribution. In order to ensure the required polymorph or version of the API is produced during the crystallisation process, a small quantity, termed ‘seed’, of the API can be introduced into a saturated solution of the API to induce crystal formation and controlled crystal growth.

Complex parameters can affect the process and the final isolated crystalline solid, of which there are several, including nucleation rate, growth rate and growth mechanism. The solid state scientist must evaluate how the crystallisation parameters of drug substance composition and solution concentration, temperature and cooling profile can be utilised to produce a crystallisation process. These will impact the API attributes of quality, form or version, habit and yield of the isolated API solid.

Bulk particle manipulation

In contrast to crystallisation, bulk particle manipulation is a ‘top down’ operation. Employed to improve drug product manufacture or to enhance drug product performance, the bulk API particle physical characteristics are modified. It is a process which reduces the particle size distribution of the API, with the desired particle size governed by the mode of administration and the drug product formulation. The efficacy of the API, as the formulated drug product, requires an understanding of the physical characteristics, such as, particle shape, size, size distribution, surface area and topography, density, compaction hygroscopicity, amorphous content, flowability, adhesiveness, cohesion and wettability of the API.

Milling and micronisation

Technologies such as milling and micronisation can control the particle size of a bulk API affording a material optimised for formulation. To enable the progression of the most suitable attributes of an API, understanding and controlling particle size for use in the drug product, is an extension of API process development and solid state investigations.

Solid form development of your API

The progress of the various solid form development elements of your API towards toxicological and clinical milestones has to be led by experienced solid state scientists and supported by analytical scientists with an in depth knowledge of a variety of techniques. Ideally, the solid form elements might be investigated in parallel, but during early stage API development, there might be numerous demands, material availability and a variety of technical considerations which can lead to sequential development flow, which can be managed between the stakeholders.

Case study: Solid form development of a new chemical entity (NCE)

A drug substance molecule was presented to Sterling for solid form development to improve aqueous solubility. The initial goal of the programme was to determine propensity of the free API to polymorphism.

Polymorphism investigations revealed the following about the drug substance:

• Eight solid form versions, seven of which were partial or stoichiometric solvates
• The supplied solid form version was the thermodynamically preferred solid form version
• The free API demonstrated limited solubility in aqueous media
• Structural determination of the preferred form revealed interaction motifs which were attributed to the low aqueous solubility of the free API

With the aim to improve the aqueous solubility of the drug substance molecule, a salt discovery programme was performed. Numerous salt candidates were identified, in addition to some counter ions affording multiple solid form versions.

Notable examples included:

• An alkali metal salt version of the API which exhibited desirable API water solubility, but was challenging to reproduce, with two different versions of the same alkali metal salt isolated affording inferior API water solubility.
• A difunctional organic counter ion salt of the API afforded significantly increased API water solubility and was reproducibly isolated. However, the molecular weight of the salt was high, and the salt was susceptible to deliquescence at greater than 70% relative humidity.

Given the challenges observed during the salt discovery programme, the free API was the preferred candidate for further development over the salts identified.

Crystallisation development was undertaken to define a controlled crystallisation procedure that afforded the preferred form of the API, with a uniform particle habit of free-flowing material that would be suitable for subsequent particle size reduction via micronisation to improve material solubility and consequently, bioavailability.

Concentration-temperature profiling of the free API, aided by in silico modelling, identified an ideal solvent mixture and conditions for an effective crystallisation that reproducibly afforded the free API as the preferred form, with desirable particle attributes that facilitated efficient particle size reduction.

For this API, all the various solid state elements were employed in order to progress the API with the preferred material attributes into stability investigations, formulation development and clinical evaluation.

Accelerating solid form API development during early investigations

Understanding the solid form behaviour of a drug substance molecule early in development is crucial to ensure the success of a viable drug product candidate. By investigating and being able to control the solid state properties of an API, downstream processing will benefit from predictable stability, solubility and optimal handling characteristics of the material during manufacture. Investing time and resource into solid state investigations and leveraging the experience of specialised scientists in the field, will afford significant advantages in particle control. Drug substance properties can also be realised, helping reduce the development timeline and cost, and increasing the likelihood of clinical success.

Find out more about Sterling’s solid state chemistry services here.

References

1. Amidon, G.L., Lennernäs, H., Shah, V.P. et al. A Theoretical Basis for a Biopharmaceutic Drug Classification: The Correlation of in Vitro Drug Product Dissolution and in Vivo Bioavailability. Pharm Res 1995; 12(3): 413–420. Find out more

2. Göke K, Lorenz T et al. Novel strategies for the formulation and processing of poorly water-soluble drugs. European Journal of Pharmaceutics and Biopharmaceutics. 2018; 126: 40-56.

3. Benet L Z. The Role of BCS (Biopharmaceutics Classification System) and BDDCS (Biopharmaceutics Drug Disposition Classification System) in Drug Development. Journal of Pharmaceutical Sciences. 2013; 102(1):34-42.

4. Butler J M, Dressman J B. The developability classification system: application of biophramaceutics concepts to formulation development. Journal of Pharmaceutical Sciences. 2010; 99(12): 4940-54.