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“Intentionally” made amorphous substance to quantify “unintentionally” produced amorphous materials:

Decades of hands-on experience



Content:

❖ Crystalline & Amorphous Materials

❖ Industrial Perspectives

❖ Three widely used, arguably best, techniques

✓ Solution Calorimetry (SolCal)

✓ Gas Perfusion Calorimetry (GPC)

✓ Dynamic Vapour Sorption (DVS)

❖ Summary



Technical:

Crystalline: Solids whose constituents (atoms,

molecules or ions) are arranged in a highly ordered

microscopic structure.

Amorphous: Solids with a lack of long-range order, highly

energetic and unstable.

Polymorphism: The ability of a solid material to exist in

multiple forms or crystal structures.



Technical:



Technical:

This means they are not same, and their

stability will be significantly different due to

their varied physical properties.

Understanding the properties in detail are the

key to the product success, especially for DPI.



Technical:

Packing diagrams of CBZ Forms I (A), II (B), III (C) and IV (D) (taken from Rodríguez-Spong et al., 2004).



Technical (Amorphous):



Why - Industrial Perspectives?:

• To achieve d90 of <5µm (often 2-3µm) PSD, milling is used.

• Milling induced disordered material, amorphous, is highly energetic and a considerable portion of these particles significantly influence the cohesive and adhesive balance (CAB) of micronised particles.

• This behaviour results in varying fine particle fraction (FPF) which ultimately affects dry powder inhaler (DPI) performance.



There is also an important aspect of milled materials that

they are heterogenous in nature. Due to the different

particle size, shape, surface area, high energetics, it

has been a challenge to produce stable DPI product

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, control over

amorphous materials, and they may assign limits for

amorphous content in batches that are to be used for

commercial purposes.




Technical – Solution Calorimetry:

Solution Calorimetry is the determination of heat

of solution when a solid is dissolved in a liquid, or

two liquids are mixed upon breaking of a glass

ampoule whereby sealed glass ampoule holds

solute in question.



Technical – Solution Calorimetry:



Technical – Solution Calorimetry (Ideal):



Technical – Solution Calorimetry (Challenges):



Solution Calorimetry (Pros & Cons):

Pros Cons

1) Wide range of solvents can be used. 1) Volatile solvent (e.g. acetone) can't

be used.2) Flexibility in quantity of mass to be

used

2) Different sealant is required for

solvents like THF, DCM and DMF.3) Flexible temperature range (e.g. 25,

35, 45°C) and vessels (e.g. 25ml,

100ml)

3) Precision calorimeter demands all

experimental processes to be precise.

4) No effect of particle size, shape etc.

as long as the sample is inside the

ampoule, it will be measured.

4) The heat of solution difference of <

20J/g between crystalline and

amorphous materials are found to be

challenging in developing good

method.5) No mixing or blending is required.



Technical – Gas Perfusion Calorimetry:

Gas Perfusion Microcalorimetry is the measurement of heat as the sample adsorbs, absorbs, crystallizes and then expels any solvent during a plasticization process.



Technical – Gas Perfusion Calorimetry:



Technical – Gas Perfusion Calorimetry (Ideal):



Technical – Gas Perfusion Calorimetry (Challenges):

Power–time data for salbutamol sulphate (both amorphous and crystalline materials are shown) when exposed to successive environments of elevated relative humidity. The response of the amorphous material is initially much greater, as it crystallizes to a monohydrate, but is actually smaller than the crystalline material in the second phase, because particle fusion has reduced its surface area.

Taken from Simon Gaisford with permission Pharmaceutical Technology Vol. 41, No. 4 Pages: 28–33



Gas Perfusion Calorimetry (Pros & Cons):

Pros Cons1) The change in power (µW)

can be measured effectively for

a very small change in sample.

1) Selective solvents can be used (e.g. DI

water, Ethanol).

2) No mixing or blending is

required.

2) Hydrates, solvates (either they are

present, or they form during experiment)

possess challenges in interpretation.

3) Flexible temperature range.

3) High mass could result in non-uniform

vapour exposure due to the narrow sample

holder.4) Effect of particle size and shape cannot be

ruled out especially at wetting process.5) Long run time, often 24 hours.



Technical – Dynamic Vapour Sorption:

Dynamic Vapour Sorption (DVS) is the determination of change in sample weight of the solid particulate sample when exposed to a vapour (e.g. DI water, ethanol, n-Octane, acetone with dry nitrogen mixed), the weight changes commonly being expressed in mass-percentage terms.



Technical – Dynamic Vapour Sorption:



Dynamic Vapour Sorption (Pros & Cons):Pros Cons

1) Wide range of solvents can be used.

1) Hydrates, solvates (either they are

present, or they form during experiment)

possess challenges in interpretation.2) Flexibility in quantity of mass especially

using metallic pan that reduces static nature.

2) Effect of particle size and shape cannot

be ruled out specially at adsorption process.

3) Flexible temperature (e.g. 25, 40°C) range.

3) Adsorption/absorption processes are

often due to the nature of materials, their

size and shapes.4) Recrystallisation (weight loss

phenomenon) is directly proportional to

amorphous material present in the sample.

4) Volatile solvent (e.g. acetone) may not

maintain %RVP accurately.

5) No mixing or blending is required. 5) Long run time.



Summary:

• 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.

• Ensures reproducible data in a robust manner. • It is good to have sensitivity but essential to have

reproducibility.



Summary:

Obtaining reproducible data and understanding the processes for these challenging systems (crystalline, amorphous, hydrate, solvate, milled samples etc.) and their responses to each specialised technique requires in depth knowledge, skills and experience.



Acknowledgements:

Prof Graham BucktonProf Simon GaisfordEx and Present ColleaguesTA Instruments



Thank you very much

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