John Mykytiuk-Solid State Manager; Simon Abbott- Milling Technical Manager, Sterling Pharma Solutions
A stable, reproducible solid form is the basis of the majority of pharmaceutical dosage forms, including tablets, capsules and inhaled products. Selecting the optimal solid form has become increasingly important in the development process for an active pharmaceutical ingredient (API), both from the manufacturing perspective, and also for its therapeutic effectiveness.
On the manufacturing side, a well-understood crystallization process giving reproducible particles will likely make filtration, drying and transfer more predictable, and should also improve the product’s stability during storage and shipping. It can also make it easier to identify batches that are outside of specification, while streamlining operations.
The API’s solid form can have a major effect on therapeutic efficacy of a drug product, as it can affect its solubility, dissolution rate and bioavailability, all of which can have an impact on how it behaves in the patient after administration. The physical properties such as density, flow and compressibility are all critical parameters for a drug product’s manufacture.
This is ever more important, as it is estimated that at least 90% of all newly discovered APIs entering the development pipeline have poor solubility.1 Nearly as many – about 85% – exist in two or more polymorphic forms,2 which can have a hugely negative effect on the manufacturing process and the therapeutic performance of the drug. And almost half of all APIs that have already reached the market were developed as salt forms,3 often to improve solubility or polymorphic stability.
So many properties of the solid form are critical for both the API manufacture and drug product formulation. If the solid-state chemists work closely with the production chemists, the requirements of the two teams can be prioritized alongside each other, maximizing the chances of a successful solid form being developed.
What is the Role of Solid-State Chemistry?
Fundamentally, the role of the solid-state chemistry team is to identify a target solid form that has the optimal physical properties, as ascertained by the formulation specialists. But solid-state experts will also be able to highlight any potential challenges that the forms might pose during the drug product development process. Taking into account all the advantages and disadvantages, a target API form should be selected that meets the needs of both manufacture and commercialization.
The team will also ensure the securing of comprehensive intellectual property (IP) claims, as this can be significant in an API, and therefore have important commercial implications; if the patent coverage is not sufficiently wide, then competitors may try to claim alternative salts, cocrystals or polymorphs as competitive products.
There are a broad range of studies and tasks that the solid-state team can carry out, depending on the requirements of both the API and the needs of the formulation team. These can include salt investigations and, if necessary, cocrystal studies, to manipulate the API’s solubility, dissolution profile and physicochemical properties. Polymorphism screenings will determine the propensity of different polymorphs of the API to form.
A pre-formulation evaluation will look at how different versions of the API’s solid form behave under different conditions. Crystallization development will be carried out to achieve the target API version for manufacture. And finally, studies on bulk particle manipulation, such as milling and micronization, will ensure that the particle size distribution can be varied.
The nature of the solid form of an API has important implications for its physical properties and, ultimately, its therapeutic efficacy, so all studies must be carried out with the requirements of the drug product formulation in mind.
Perhaps the most important factor to investigate is the make-up of the crystals. Different packing arrangements can lead to significant differences in the API’s physical and chemical properties, ultimately affecting the drug’s efficacy. Good solubility is important: if the API particles do not readily dissolve, their absorption in the body will be limited, impeding their ability to reach the therapeutic target site. And different polymorphs of the API can behave very differently not only in the body, but also during manufacturing, with different physical properties potentially affecting filtration, drying and stability.
Particle shape is important too, as larger particles can create additional solubility issues. The shape and size of the particles can affect their distribution in a finished solid dosage form, which may lead to irregular and inconsistent doses. It is also critical to minimize any impurities early on in the development process, either eliminating them entirely, or controlling them during manufacture, as even small variations can impact the physical properties of the drug substance.
Identification Techniques
There are numerous techniques to inform the identification and selection of the optimal solid form. The most important of which are salt and cocrystal screenings, polymorphism screenings, and pre-formulation evaluation. Any, or all of these, may be appropriate, depending on the nature of the API and the requirements for the solid form.
If a polymorphism screen does not identify a form that has the ideal properties and is suitable, then other techniques need to be tried. Usually, the first option for a problematic API is a screen for an appropriate salt form and, if that is not possible or unsuccessful, a cocrystal. The aim of these studies and screens is to find a solid form that offers greater solubility than that of the free API.
To carry out a salt study, fi rst the free API is characterized as a reference, and used to identify potential solvents and anti-solvents. Then, a panel of counterions will be assessed, with their nature depending on the acid dissociation constant (pKa) of the API. Any isolated solids will be characterized to identify hits, using techniques such as X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), nuclear magnetic resonance (NMR), as well as Raman or infrared spectroscopy.
If the API is not amenable to salt formation, either because it has no ionizable groups or because one simply cannot be found, then a cocrystal may be appropriate. Again, a screen will be run with a selection of appropriate cocrystal-forming molecules. Any that are identified will, once more, be fully characterized.
Regardless of whether the desired properties are achieved with a simple crystal, a salt, or a cocrystal, then a polymorph screen will still be required to ensure the most stable or suitable crystal form has been selected, and one that it is not prone to interconverting into another polymorph form. This step is essential to meet regulatory requirements. For example, equilibration experiments should be done in a range of solvents to assess whether any solids are solvates, hydrates, or new polymorphic forms.
If there are multiple promising solid forms identified by the various screens, pre-formulation evaluation can assist in selecting the best option. These can be carried out in conjunction with the earlier screenings, or as a separate development step later on. These studies will typically assess factors such as solubility in aqueous media and simple formulation vehicles, stability under accelerated storage conditions, behavior during compression and particle size reduction, and powder flow characteristics. Any solid forms that show unsuitability in any of these tests can safely be eliminated from further consideration.
Particle Size Engineering
The final step of producing an API solid for formulation development or manufacture is crystallization. Many competing characteristics must be addressed during crystallization, including chemical purity, API version (polymorph), and particle shape and size. Ultimately, the goal is to develop a crystallization process that reproducibly gives the same quality material that meets the needs of the drug product.
Ideally, the crystalline material that is the direct product of the manufacturing process would be perfect for the needs of the drug formulation team. However, in reality, this is unusual and further manipulation steps will often be necessary to produce APIs with physical characteristics that are suitable to create a successful oral dosage form.
Crystallization alone may not always provide a suitable particle size distribution, so altering the shape and size of the bulk particles, and making the material more homogeneous, can improve manufacture and even enhance API performance. In contrast to ‘bottom up’ crystallization development, bulk particle manipulation is very much a ‘top down’ operation. Milling and micronization are commonly used to ensure that the API’s particles are suitable for drug product formulation to ensure consistent dosage.
Smaller particles may prove more soluble and can help improve the molecule’s bioavailability, and changing the shape of the crystals can alter handling characteristics.
Several methods of particle size reduction can be used. Impact milling, for example, is good for materials where a larger particle size, typically above 30 µm, is required. There are multiple different adaptors and screens that can be used to generate different particle sizes to suit formulation needs. However, the particle size distribution is likely to be fairly wide, because of a lack of control of the top-end particles, and friction can also result in the mills generating heat, which may also cause problems for temperature-sensitive APIs.
Another method is jet milling, which is an efficient option for materials where a finer particle size, down to about 10 µm, is desired, with a tight distribution curve. This method is particularly appropriate for pulmonary drug formulations, where particles sizes need to be less than 5 μm. This technique does however use compressed gas, which leads to relatively high running costs.
Wet milling can be an appropriate method for materials that are more hazardous in solid form, as they are made into a slurry, with no airborne particles. However, this necessitates subsequent isolation and drying steps that can cause follow-on problems such as hard agglomerations, which are undesirable.
Better Together
It is a distinct advantage if both API manufacture and solid form services take place within the same company – and even more so, if the two functions are in the same location. It minimizes the amount of tech transfer that is required, allows harmonized development plans to be generated and expedited, and reduces the response time to any problems that might arise with a solid form. This is the case for new products, with both manufacturing and solid form experts finding it far easier to collaborate to find a satisfactory outcome that meets the formulation development or manufacturing needs, or in a case where an established API is being repurposed, perhaps by delivery via an alternate route.
Either way, the real value in having integrated manufacturing and solid form teams is that the entire process should go more smoothly and quickly, which is beneficial and more cost-effective for the customer. If all operations take place in individual silos, without effective lines of communication and common understanding, there is a significant risk that if challenges arise, the delays will be even more substantial. Integrated services, and open information sharing means projects are more likely to keep to the all-important project timelines.
References
- N.A. Patel Mat. Sci. Res. India, doi: 10.13005/msri/180204
- L. Baraldi et al. Anal. Chem. 2021, 93, 9049
- A. Serajuddin Adv. Drug Del. Rev. 2007, 59, 603
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