An investigation into the stability and solubility of amorphous solid dispersion of BCS class II drugs Shrawan Baghel, WIT

Crystallization Polymer selection Manufacturing Stable ASD products

An investigation into the crystallization tendency/kinetics of amorphous active pharmaceutical ingredients: A case study with dipyridamole and cinnarizine 1. Fragility a.Thermodynamic fragility b.Dynamic fragility (i) Extrapolation of configurational entropy to zero (ii) Heating rate dependence of glass transition temperature 2. Glass forming ability 3. Isothermal crystallization kinetics 4. Non-isothermal crystallization kinetics 5. Stability studies of amorphous solid dispersion

1. Fragility a.Thermodynamic fragility (m T ) b.Dynamic fragility (i) Extrapolation of configurational entropy to zero (m DCE ) (ii) Heating rate dependence of glass transition temperature (m DTg ) Fragility and mean relaxation time of model drugs *T o, T K and Г are Kauzmann temperature, fictive temperature and relaxation time respectively. m < 100 = Fragile glassD < 10 = Fragile glass m > 100 = Strong glassD > 10 = Strong glass

2. Glass forming ability T red values were found to increase at higher heating rates which suggest that crystallization tendency for both the model drugs increases with an increase in heating rate. Moreover, at all heating rates, CNZ was found to have lower GFA as compared to DPM which is in agreement with the molecular mobility based estimation of crystallization tendency of amorphous model compounds. FRAGILE GLASSES HAVE POOR GLASS FORMING ABILITY

3. Isothermal crystallization kinetics Crystallization temperature (T c ), Avrami constant (K), Avrami exponent (n) and activation energy (E a ) of amorphous model drugs Values of Avrami exponent (n) and expected crystallization mechanism

4. Non-isothermal crystallization kinetics Effect of heating rate on activation energy of crystallization of amorphous dipyridamole (a) and cinnarizine (b) obtained by fitting nucleation and diffusion models of different orders. Model-free kinetics for amorphous dipyridamole (a) and cinnarizine (b) calculated by Kissinger- Akahira-Sunose isoconversional kinetics to identify the most suitable kinetic model; (n=3) *JMAEK (n=2) (blue), 1D diffusion (red), First order reaction (green), Power law (n=1/2) (purple) and 1D phase boundary reaction (light blue) CRYSTALLIZATION MECHANISM OF BOTH THE MODEL COMPOUNDS DEPENDS ON THE HEATING RATE

5. Stability studies of amorphous solid dispersion CNZ ASD – Unstable – Highly fragile, poor glass forming ability and low crystallization activation energy (nucleation based mechanism)

Theoretical and experimental investigation of drug-polymer interaction and miscibility 1.Prediction of drug polymer miscibility from solubility parameter approach 2.Drug-polymer binary interaction parameter from melting point depression data 3.Phase diagram 4.Drug-polymer-water ternary interaction parameter 5.Role of polymers in maintaining and prolonging drug supersaturation in aqueous medium

1.Prediction of drug polymer miscibility from solubility parameter approach Solubility parameter difference < 7 MPa 1/2 = Miscible System Solubility parameters differing by more than 10 MPa 1/2 = Immiscible system

3. Phase diagram (a) DPM-PVP; (b) DPM-PAA; (c) (CNZ-PVP and (d) CNZ- PAA

Antiplasticization effect: Phase diagram predicted unstability for Systems at higher drug loading However DPM-PVP, DPM-PAA and CNZ-PAA are found to be stable up to 65% (w/w) drug loading This could be explained from antiplasticization effect of polymer on drug within dispersion Positive deviation = Strong heteronuclear interactions Negative deviation = Strong homonuclear interactions Only CNZ-PVP systems shows negative deviation which explains its crystallization at higher drug loading (50 and 65 % w/w) PAA is found to be more effective in stabilizing model drugs compared to PVP FT-IR studies further confirmed the presence of stronger drug- polymer interaction within DPM-PVP, DPM-PAA and CNZ-PAA systems whereas CNZ-PVP spectra does reveal any significant interaction (a)DPM-PVP; (b) DPM-PAA; (c) (CNZ-PVP and (d) CNZ-PAA Blue line indicates T g values predicted from Gordon-Taylor Equation; Red dots are experimentally obtained values

5. Role of polymers in maintaining and prolonging drug supersaturation in aqueous medium The value of SP for different drug-polymer systems used in this study are found to be 0.17, 0.98, 0.06 and 0.94 for DPM-PVP, DPM-PAA, CNZ-PVP and CNZ-PAA systems, respectively. Thus DPM-PAA system performed best in maintaining and prolonging drug supersaturation in aqueous medium which was attributed to the drug’s low crystallization tendency, the strong DPM-PAA interaction, the robustness of this interaction against water and the ability of PAA in maintaining DPM supersaturation.

DPM --- F-H interaction parameter with PVP and PAA are and hydrophobic nature (log P = 3.71) prevents its interaction with water to retard crystallization --- Both situations may lead to a strong adsorption of polymers to the drug surface CNZ --- forms strong h-bond with PAA and thus its supersaturation is maintained in PAA solution --- Hydrophobic nature (log P = 5.71) could also favours its interaction with PAA in the solution state. Although, the physical interaction between CNZ and PVP (-1.11) is nearly equal to that between CNZ and PAA (-1.51), the more hydrophilic nature of PVP and lack of H-bonding could reduce its interaction with hydrophobic CNZ, thus negates its ability to prevent CNZ crystallization and maintain its supersaturation in solution. The initial significantly higher concentration of CNZ in PVP solution compared to solution without PVP may be attributed to retardation in crystallization due to increase in fluid viscosity surrounding solubilised drug.

Thank you for your time. Any questions? Dr. Niall O’Reilly Dr. Helen Fox