Milling-induced disordered (amorphous) material is highly energetic and a considerable portion of these particles significantly influence the cohesive and adhesive balance (CAB) of micronized particles.
This behaviour results in varying fine particle fraction (FPF), which ultimately affects dry powder inhaler (DPI) performance. Milled particles are also heterogeneous in nature, they differ in particle size, shape, surface area, and energetics.
These characteristics make it challenging to produce stable DPI products without a deep understanding of the physical properties of milled and un-milled samples, their behaviour and control over their processing. It is reasonable for the regulatory authorities (e.g. FDA, MHRA) to seek a suitable analytical method to quantify amorphous content and they may assign limits for amorphous content in batches that are to be used for commercial purposes. Hence, M2M Pharma is set up to be The Amorphous Content Determination Specialists by having its in-house technology coupled with decades of hands-on experience in handling 1000s of batches across 10s of APIs.
Solution Calorimetry: This measures the heat of solution upon dissolvation of solute into the solvent.
As crystalline materials exhibit crystal lattice arrangement and it would require higher energy (endothermic) to break its lattice but "Not" for amorphous materials as they don’t have long ordered crystal lattice arrangement (exothermic) and the difference between these two responses remained our key interest.
If this difference is > 20J/g, then M2M Pharma can develop a reproducible method for your sample. This is one of the best techniques for quantifying amorphous content in very small level (ca. 1%w/w). We have developed methods using this technique for some of the most challenging inhaled APIs, hormones over last two decades.
Hence, due to the high volume of workload, we have multichannel solution calorimeters with a flexibility of using in TAM2277 and TAMIII. Our recent research shows that 25ml vessel produces better data than 100ml vessel, that also ensures “Green Chemistry” and we now routinely use 25ml vessel alongside 100ml.
This measure change in power (µW) at a constant temperature and this change is related to wetting and drying response of solids under varying %RH or %RVP. Our perfusion calorimeter is attached to TAMIII. We have decades of experience in developing methods for various inhaled APIs.
This measure change in weight upon exposure to varying %RH at a constant temperature. We often use this technique for amorphous content determination by measuring recrystallisation (% weight loss) using either DI water or other organic solvents (e.g. Ethanol, n-Octane etc.).
We also use this for routine hygroscopicity measurement to predict storage condition for solid samples. Again, we have decades of experience in developing methods for various inhaled APIs.
There is no standard method to quantify amorphous materials in a crystalline bulk for pharmaceutical solids. As all such particles have different physicochemical properties, it is important that the method is developed as per the sensitivity of the solids to the technique which ensures reproducible data in a robust manner.
BET-SSA: This measures surface area for solids. As we handle micronised batches, this technique is routinely used for measuring surface area.
Pycnometer is used for determining the true density of solids.
This is a “gold standard” physical form identification technique. At M2M, we use this for phase identification, quantification, batch to batch variation, etc.
Making Amorphous Form:
We have never failed to make any amorphous form for an API. Our preferred technique is quench cooling, as it is a dry method, and we can reproducibly make g of amorphous material for you. We also use milling, cryo milling, spray drying, rotary evaporation, freeze drying etc.
TGA: It measures % of weight change upon heating. This is routinely used for quantification of adsorbed and absorbed moisture and/or solvents, hydrate/solvate etc. It also provides an indication of melting and/or degradation temperature etc.
DSC: It measures change in power signal due to the endothermic and exothermic processes of solids upon heating. We routinely use this for determination of melting point temperature, glass transition temperature, crystallization temperature, solid state transitions.
Particle size reduction technology using micro-mill is a very efficient way to obtain even micron sized particles in a continuous process. We can mill mg of sample at early stage of development to demonstrate reduction in particle size.
Polarised light microscopy is used to get an indication on particle size and shape.
Surface Energy Determination by iGC-SEA: M2M has an exclusive access and expertise in measuring surface energy, cohesive and adhesive balance for micronised particles. This is a very specialised technique routinely used for characterising inhaled API and formulations.
Single Crystal Determination: M2M has access to Synchrotron system for Solving crystal structure of solids. Our team has number of publications in solving crystal structure from good quality powder data.
M2M has an exclusive access to use this technique with Renishaw (pictures are taken from Renishaw with a permission). We have carried out numerous imaging projects and our clients were very impressed with the quality of data and quantification level obtained using this machine.