Author: rddennehy

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What makes a good crystallization process?

 The question arose when I was designing a crystallisation process for a particularly recalcitrant API (Active Pharmaceutical Ingredient). Once one problem had been solved, another was identified, as can often be the case within material sciences. For example, crystallisation from aqueous alcohols gave good (but not excellent) yields, but in some compositions, oiling occurred. Addressing the oiling required better control of supersaturation and slower cooling, but then the clock was ticking with respect to degradation of the API in the solvent. In the end, a process could be defined but it was like walking a tightrope and a high degree of control was needed to ensure the right quality of product was delivered in good yield. And then, of course, the inevitable happened: a new polymorph was found. It was then back to the beginning again!  

However, I do think it’s useful to try and articulate what the characteristics of a good crystallisation process really are. So, I decided to try and tackle my own question. I would be interested to hear what you think makes a good crystallisation process, and whether you agree with me on my ideas below…  

The first thing to say is that the crystallisation needs to deliver the API with the desired attributes. Some of these will be defined as Critical Quality Attributes (CQAs), whilst others may be needed from an API or formulation manufacturability perspective but may not find their way into the API specification.  

Here’s a list of some common API attributes, it’s not exhaustive and there are many other API properties that might be measured and targeted for control, but these are some of the most frequent: 

  • Impurity profile 
  • Assay 
  • Solid state form 
  • Residual solvent content 
  • Colour 
  • Particle size 
  • Morphology 
  • Bulk density 
  • Powder flow 

Besides the properties of the API, there are aspects of a ‘good’ process which broadly pertain to the selection of the solvent, such as: 

  • It is volume efficient 
  • It is high yielding 
  • Solvent can be recovered  
  • Environmental, Health & Safety impacts of solvent are less significant 
  • The API is sufficiently stable in the solvent 
  • The solvent can be removed on drying 

The potential for API degradation is one aspect that doesn’t receive as much attention as it should. Degradation of a complex organic molecule in a solvent, particularly at temperature, should be expected. If required, more detailed kinetic studies of degradation might be conducted so the operating window for the process is well understood. 

Finally, a ‘good’ crystallisation process will also have the following characteristics which are somewhat more difficult to place into a category. They are neither a function of the output properties or solely of the solvent selection. Nevertheless, they are still important: 

  • Cycle time is sufficiently short 
  • Reversibility: The solute can be taken back into solution, if needed, without isolation 
  • It’s simple: The fewer process steps the better 
  • Can be polish filtered to support GMP 
  • It Is tolerant of variable input 
  • Can be integrated back into the penultimate step of chemistry 
  • Provides a reproducible output 
  • Can be scaled easily 
  • A control strategy can be articulated  
  • Oiling-out is absent 
  • Filters with ease 

The approach in designing a crystallisation process can and should be phase appropriate; some of these characteristics don’t need to be met for a Phase I supply. They may however, become more important for a process at multi-tonne scale in a commercial manufacturing plant. Also, it’s important to note that finding the perfect process is unlikely. Some characteristics are more important than others and might need to be traded-off so long as the API CQAs aren’t compromised. 

This is my list of what I deem makes a good crystallisation process. Does it look the same as yours?  

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Seeding: A simple but effective method for crystallization control

Seeding is probably the most common technique for controlling the solid state and physical properties attributes of a drug molecule. But what needs to be considered when using seed crystals?

Identify what needs to be controlled

There are 2 main reasons for using seeding in pharmaceutical crystallization:

Control of solid-state form is the most common reason. The assumption being that the form of the product is templated by the addition of the seeds. Without seeding, nucleation may generate an undesired solid-state form which alters solubility and formulation performance.

Control of particle size is less common in my experience but is a much more elegant solution to control of Particle size distribution (PSD) then the alternatives, milling or micronisation. Dry milling methods add process complexity, are dusty and hence require containment.

In addition, seeding may be utilised to better control supersaturation where this is linked to a specific undesirable effect such as impurity incorporation, agglomeration, or oiling.

The Seed Source

A variety of seed sources can be used:

  1. ‘As-is’ seeds from a specific batch –a batch is identified and used to seed many batches.
  2. Daughter seeding- seeds from the preceding batch are used for a specific crystallization and this is repeated with subsequent batches.
  3. Milling or micronisation- A batch is size reduced and used to seed many batches.
  4. Sieve fractions- A batch is sieved to deliver a fraction and used to seed many batches.

Selecting the seed source depends on the attributes in the product that require control. For solid state form, any seed source can be used. For control of PSD, the seed itself should be size controlled and hence only milling, micronisation or sieve fractions are viable options. Whichever source is selected, the seed batch should be well characterised using a battery of analytical techniques to ensure phase purity and appropriate PSD.

The use of daughter seeding carries the risk of progressive build up in the seed of an undesired solid-state form and this option should be used very cautiously.

Process Development

Ideally, the solid-state form landscape of the molecule should be well understood before seeding is instituted. As well as this, the process, preferable a cooling crystallisation, should be well designed with selection of the appropriate solvent and determination of the solubility curve and metastable zone width. With this data, an appropriate point on the solubility curve can be determined for seed introduction. A simple rule of thumb is to seed 1/3rd into the metastable zone. The trajectory of the crystallisation should then be controlled to limit the build-up of supersaturation and hence avoid nucleation and limit agglomeration. The objective is always to maximise growth of the seed crystals. Where PSD control is an objective, the effect of adding increasing amounts of seed should be studied. The crystallization can be biased towards crystal growth if a correlation is found between output PSD and seed loading. If no correlation is achieved, then nucleation may dominate the crystallization and an alternate strategy will need to be investigated. Once the seed loading has been established the impact of agitation should be assessed. This plays a role particularly for agglomeration and attrition and both should be limited.  The process can then be cautiously scaled using the standard consideration of geometric similarity and using appropriate scaling parameters with the output PSD being measured at each step.

Introducing seeds into the crystallisation

Seed crystals need to be introduced into as homogeneous environment as possible and carefully grown, avoiding excessive build-up of supersaturation in the bulk. This is addressed partially by appropriate cooling and suspension conditions, but how the seeds are introduced is also important. The seed crystals should be well dispersed at the point of addition and slurrying the seeds in a solvent is an ideal method to do this. Slurrying may alter the seed physical properties so this step should also be studied, for example, using laser diffraction and SEM. The seed slurry should be introduced into a portion of the vessel which is the well mixed and CFD modelling may be useful in assessing the best point of addition.

Stability of the seed source

A shelf life for the seed should be nominated and supported by physical properties data indicating that the seed is stable and functional over time. Use testing of the seeds in the crystallisation may also provide useful data to support shelf life.

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In Particle Engineering, don’t forget the Formulation.

Many years ago I was involved in a capability project to make capsule formulations that contain JUST API. Surprisingly, we got quite close. In one case, we required only the addition of Mag Stearate to keep the dosator from seizing-up; no other excipients were needed. All the desired Physical Properties (bulk density, flow, solid state form) were engineered into a reproducible and scaleable API process. It was a great example of Particle Engineering.

However, it wasn’t a general approach. For the vast majority of cases, delivering not only flowability and density but wettability, dispersion, stability and dissolution with just the API and within the constraints of an advancing project timeline was too big an ask.

I learnt from this experience that the selection of excipients and the unit operations that bring all of these together to create the formulation should be considered as ‘levers’ in the product design alongside Particle Engineering. Doing so provides huge room for manoeuvre in creating the right product without setting unrealistic requirements of the Particle forming step.

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Solid State, Crystallisation and your Drug

robert@apiparticle.com

Problems with API solid state are often overlooked in drug development. Selecting a sub-optimal version, lack of polymorph control, and poor design of the API step can halt a clinical program or delay commercialisation.

Having managed a broad portfolio of API projects with accountability for crystallisation and solid state from pre-phase 1 to manufacturing, if your drug has these sorts of problems, then feel free to contact me.