Author: Robert Dennehy

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The Intriguing Polymorphism of Albendazole

Polymorphism, where molecules can pack in different ways in the crystal, is one of the most important considerations in drug development as different packing arrangements can exhibit different solubility in-vivo and hence impact safety and efficacy.  Albendazole is a commonly used Anti-helminthic for the treatment of such conditions as cystic hydatid disease in both humans and animals. There are two main types of polymorphism; conformational polymorphism where the conformation of the individual molecules differs and this leads to different packing in the lattice, and packing polymorphism, where the molecular confirmation is the same, but individual molecules are packed differently in the lattice.

A B C

Figure 1. Structures A and B are related through packing polymorphism, whereas Structures A and C are related through conformational polymorphism.

Albendazole however, is a drug that falls into neither of these 2 categories. The commercial form of the drug is form 1. However, another polymorph, denoted form 2, also exists. The 2 polymorphs differ not merely through molecular confirmation or packing, but through proton transfer. In fact, the 2 forms are composed of molecules that are chemically different, Form 1 being the Amino form, and Form 2 being the Imino form, both forms being Tautomers of each other1. As they are chemically different, they are technically not even polymorphs! Unfortunately, there doesn’t seem to be a consensus on the descriptive term in the literature, and such examples of proton transfer can be described as ‘Desmotropes’ or as polymorphs. Figure 2 shows the chemical structure of the Tautomers. The picture is further complicated by disorder of the propylthio chain seen in the Xray crystal structure of Form 2; hence the representation in the structural formula in 2 positions on the Benzimidazole ring.

Figure 2. Tautomers of Albendazole. a. Amino Tautomer. B. Imino Tautomer showing disordered propylthio side chain (note, this is not disubstitution).

Delving into the literature more widely, polymorphs related through tautomerism are quite common. A further example is the anti-hypertensive Irbersartan2. In this case, the Forms are related to different protonation on the Tetrazole ring; Form A from the 1H tautomer and Form B from the 2H tautomer. As might be expected, there is a relationship between predominant tautomers in solution and the outcome of crystallisation from specific solvents. In a very elegant piece of work, using solvents of high relative permittivity and dipole moment, tends to lead to the crystallisation of Form B, whilst the reverse is true for Form A. The solvent favouring one tautomer over another in solution and hence leading to crystallisation of the specific form.

The whole area of polymorphs related through proton transfer, like Albendazole and Irbersartan, has been reviewed and the various scenarios classified in detail3.  This paper shows the complexity encountered when proton transfer and tautomerism are overlayed with polymorphism.

References

  1. Enantiotropically Related Albendazole Polymorphs. Marco B. Pranzo, Dyanne Cruickshank, Massimo Coruzzi, Mino R. Caira, Ruggero Bettini. J Pharm Sci, 2010, 99 (9) 3731.
  2. The effect of solution environment and the electrostatic factor on the crystallisation of desmotropes of Irbesartan. Andrea M. Araya-Sibajaet al.  RSC Adv, 2019, 9, 5244.
  3. A to Z of polymorphs related by proton transfer. Amy Woods-Ryan, Cheryl L. Doherty, Aurora J. Cruz-Cabeza. Cryst Eng Comm, 2023, 25, 2845.
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Should I develop the hydrate form of my drug?

Hydration is a common phenomenon, affecting as many as 38% of drug molecules1.

There are plenty of hydrated drugs on the market, but how can an informed choice be made of which version to develop, the hydrate or the anhydrate? 

Understand the system.

The first question to ask is ‘Do I have a hydrate?’ and as many polymorph screens do not specifically seek out hydrated versions, this may not be obvious. Aqueous/organic solvent mixtures should be incorporated into any polymorph screen that supports a version decision.  If the polymorph screen doesn’t furnish new hydrated forms, then computational approaches such as the Cambridge Crystallographic Data Centre’s (CCDC)  Hydrate Analyser can be used to assess the potential risk and might stimulate more in-depth experimental searches2. Conversion to a hydrate occurs once a critical water activity is reached. This is an important value and can be measured using dynamic vapour sorption (DVS) although as a kinetic measurement, DVS may not detect water uptake if it is slow 3. Better, is to slurry the API in aqueous/organic mixtures of known water activity and analyse the solid after equilibrating for a nominal period (DSC, TG, DVS, XRPD and of course KF) 4. Knowing the critical water activity is crucial in understanding the controls which might be required during manufacturing, storage and in-use, both for the API and the formulation.  Also, Single Crystal X-ray Diffraction can provide an effective basis to rationalize the observed hydration/dehydration pathways. Hydrates in which the water is stable over a range of humidities and temperatures are much easier to develop than where hydration is partial, easily reversible, or where water is lost at typical conditions that might be encountered in a manufacturing plant. 

How do the bioavailability, manufacturability and stability compare?

The hydrate normally has lower aqueous solubility than the anhydrate so might not be selected based purely on this criterion5. However, if the solubility absorbable dose can be achieved, then the hydrate should still be a potential candidate for development. This presents an interesting question. Should the hydrate be developed in preference to the anhydrate as dehydration will lead to higher not lower solubility? The solubility though isn’t the only consideration in formulation performance. Hydration during tablet disintegration can negatively impact dissolution rate and this might disfavour selection of the anhydrate as the developable version. This is seen in the case of Theophylline where the growth of an extreme hydrate habit impedes tablet dissolution6. Establishing potency of the formulation should also be considered, particularly where water gain and loss is facile; how much of the drug needs to be weighed-out when the formulation is manufactured? The other typical physical properties that make an API well behaved such as habit, powder flow, compressibility etc. should also be assessed as part of the decision7.  Finally, the chemical stability of the anhydrate and hydrate may differ.

 Will I have to control the hydration state in manufacturing, storage and in-use?

The need for control is also an important consideration in deciding between a hydrate and anhydrate.  Humidity and temperature controls can introduce considerable complexity. In the API plant, the crystallisation, isolation and drying of the API might require a discrete step to achieve the desired solid state form and this might need to be maintained in bulk storage leading to a more complicated pack. Ambient humidity and temperature might require control during the manufacture of the formulation. More extreme conditions, for example less that 20% RH or more than 80% RH are difficult to achieve. Finally, in-use stability needs to be considered to ensure that the formulation is consistent with the label claim. All of this may require sophisticated and validated analytical methods to confirm the degree of hydration. For low dose compounds, particularly in the formulation, this presents a real challenge due to limits of detection.

To summarise, hydrate versions of drugs can be developed but the system needs to be understood and the impact of hydration state on the bioavailability, stability and manufacturability of the API and the formulation assessed. The final decision may be far from straightforward and may require trade-offs between optimum physical properties versus the control needed in manufacturing, storage and in-use.

References

  1. Estimates of how likely hydration is for molecular crystals vary. A survey of the Cambridge Structural Database showed 6.5% of structures were hydrated. See Motherwell http://dx.doi.org/10.1039/b612529. However, it must be assumed that not all structures are lodged in the database. The review from Stahly https://doi.org/10.1021/cg060838j uses polymorph screening statistics and is quoted here.
  2. For a review of Mercury 4.0 which includes the hydrate analyser, see https://dx.doi.org/10.1107%2FS1600576719014092
  3. See Edens and Newman in Polymorphism in the Pharmaceutical Industry p.235 ISBN 3-527-31146-7.
  4. For a comprehensive review of experimental techniques, see https://doi.org/10.1002/jps.21187
  5. See Higuchi https://doi.org/10.1002/jps.2600520815
  6. Hydrate formation for Theophylline can occur during wet massing if granulation is used in the formulation, or, at the point of tablet disintegration. https://doi.org/10.1016/0378-5173(92)90144-Q
  7. For an example of differences in tabletability directly ascribed to hydration, see the example of sodium naproxen. https://doi.org/10.1016/j.ijpharm.2010.01.036
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Should I develop a separate API step in my synthesis?

When developing the API forming step, few questions generate stronger opinions.

The crystallisation scientist is literally caught in the middle between the formulator, looking for consistent physical properties, and the synthetic chemist, focussed on high yield and a simpler route.

This is a question that is project specific but here are some points to consider.

At the outset, develop a separate API forming step

It’s much easier to develop a well understood process where the inputs themselves are fixed. The basic information and decisions, like solvent selection, solubility curve, metastable zone width, seeding parameters, scale sensitivity, polymorphism studies, formulation sensitivity etc. can be made without any concern of ‘Perhaps it was the impurity profile that made xyz happen!’

Decoupling the API forming step from the synthesis steps allows the synthetic chemist to focus on getting the purity and yield right without having to worry about the potential change in physical properties impacting the formulation.

If possible, back-integrate the API forming step into the last synthetic step

This where the really hard work starts. The advantages of having a combined synthetic and API forming step are obvious in terms of yield and potential reduction in complexity. However, it requires the synthesis and the formulation step, as well as the API step, to be well understood. Depending on the clinical timeframe, there may not be the time to do this at all.

Some criteria that might be used to help with the decision to back-integrate are laid out below. Answering ‘yes’ to most of these is more likely to lead to success:

  • Cost of goods is high
  • Clinical timeline is longer
  • API loading in formulation is low
  • Formulation is a simple immediate release oral solid dosage form
  • The purity and concentration from the chemical step can be easily measured and controlled
  • The formulation is less sensitive to changes in API physical properties

Much of this boils-down to the reproducibility of the synthetic step and the formulation sensitivity.

A real-life project example

This isn’t the place for a full development history report, but this is a real example. This API had a problem with high fines content causing punch sticking on the tablet press. A separate API forming step (single solvent, seeded, cooling cryst) was developed and demonstrated at plant scale and shown to give highly consistent PSD.

In terms of the criteria set out above, the cost of goods was high, the clinical timeline was long and the formulation was simple. However, the API loading was very high (80%) and the formulation was sensitive to changes in physical properties.  Crucially though, the final synthetic step could be well controlled in terms of purity and concentration. Weighing up all of these factors, the recommendation was to combine the final chemical step with the API crystallisation.

This was successful and the combined process could deliver a controlled and consistent PSD. The process was further developed in terms of QbD, and is now in commercial supply.

To summarise, always develop a separate API forming step at the beginning and analyse the risks in your project carefully before developing a combined final step. Good luck!

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Why has my salt screen given me so few hits?

Finding the right version of a drug is one of the most important decisions made in development. Often however, the salt screen provides far fewer hits than might be expected and sometimes none at all. As proton transfer is the fastest reaction in organic chemistry, this isn’t due to problems of reaction rate. I had a recent example of this and it made me think about some possible reasons.

1. Degradation

The API purity in the early stage of development is typically 98-99%. In my own experience, crystallisation can be inhibited at less than 95% which means that if the parent degrades even a little during the course of the salt screening experiment, then a ‘hit’ won’t be obtained.

It’s important therefore to understand solution stability and design the screen to accommodate this.

2. Is the difference in pKa between the acid and base really greater than 2 units?

It is generally accepted that a difference of at least 2pka units between the parent and the salt former is needed for complete proton transfer. However, these pKa values are generally measured or estimated in aqueous systems and not in the mixed aqueous/organic solvents used in the typical salt screen. Roger Davey et al1 performed a fantastic piece of research 13 years ago forming salts of Ephedrine (pKa 9.74). For weak acids, the actual pKa in organic solvents was shifted markedly compared to the pKa measured in water. This meant that in many cases a salt couldn’t form as protonation wasn’t complete. Consequently, those conditions returned a negative hit in the screen.

The pKa of weak acids in organic solvents can be estimated using a number of methods,2 could these be applied routinely in screen design?

3. What about pHmax?

The pHmax3, calculated from the solution speciation, the solubility product of the salt (Ksp) and the intrinsic solubility, is also an important value. For a weakly basic parent and an acid salt former, the salt is only stable in solution at a pH lower than the pHmax (the converse being true for acidic parent molecules). So for systems where the pHmax is relatively low, only strong acids will produce a hit.

Of course, Ksp won’t be known for a species that has never yet been crystallised, but the intrinsic solubility (so long as the parent has been crystallised at reasonable purity) and the speciation, will be known. So an estimate of the pHmax would focus the selection of salt formers used in the screen and increase the probability of getting hits, and hits that will survive the rigours of product development without dissociating once formulated.

To conclude, the number of hits in a salt screen could be improved by better understanding of degradation and exclusion of those conditions where this is particularly pronounced. The pKa values of the parent and the salt former in organic solvents should be accounted for and should differ by at least 2 units. Finally, the pHmax should be estimated and those experiments where dissociation is likely, should be excluded.

If all of this is implemented the problem becomes one of facilitating nucleation and crystal growth. Perhaps a subject for another day.

  1. Black, S.N., Collier, E.A., Davey, R.J. and Roberts, R.J. (2007), Structure, solubility, screening, and synthesis of molecular salts. J. Pharm. Sci., 96: 1053-1068.
  2. Leito, I. et al. (2018), pKa values in organic chemistry – Making maximum use of the available data.  Tetrahedron Letters 59 (42): 3738-3748
  3. Serajuddin, A.T.M. (2007) Salt Formation to Improve Drug Solubility. Advanced Drug Delivery Reviews, 59: 603-616.

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The Bioenhancement Jungle

So you have a great drug molecule and need to turn it into a solid to progress clinical trials and product development. The molecule itself crystallises but the solubility is just too low. This is when Bioenhancement, which basically entails increasing drug solubility, can be deployed. There are a myriad of techniques out there and finding the right path is tough, hence the title of this post.

Techniques include the following:

  • Salt formation – used widely and enhances aqueous solubility through ionisation.
  • Particle size reduction – Normally through micronisation, increases available surface area to dissolve the drug more quickly but doesn’t effect equilibrium solubility.
  • Cocrystal formation – applied much less widely than salt formation due to issues with dissociation, precedence and increased molecular weight.
  • Amorphous dispersion – normally the first stop if a crystalline soluble version can’t be identified. Amorphous solids have higher solubility relative to crystalline solids as there is no lattice energy to overcome on dissolution. But. there is a potential penalty to pay in physical and chemical stability.
  • Nanomilling – reducing particles to sub-micron sizes increases the equilibrium solubility but particle growth is a risk so nanoparticles normally require some degree of stabilisation in the formulation. Complex manufacturing.

My advice is always to make sure the salt formation work is performed credibly and if that doesn’t deliver the solubility, stability and manufacturability you need, then pick your way carefully through the jungle.