Dr Mingzhong Li School of Pharmacy, De Montfort University

Transcription

1 Dr Mingzhong Li School of Pharmacy, De Montfort University

2 Introduction Toxicity Lack of efficacy Poor biopharmaceutical properties APIs Dosage forms Routes of administration Less than 1% of APIs into the market Low solubility/dissolution rates of APIs: BCS II Salt formation Particle size reduction: micronisation/nanocrystals Amorphisation Cyclodextrin complexation And so on Pharmaceutical cocrystals have emerges as a potential approach to enhance solubility/dissolution rates

3 Pharmaceutical cocrystals A Pharmaceutical cocrystal is crystalline material that contains two or more components (one of the component is an API) that are present in definite stoichiometric amounts and the co-crystal components are discrete neutral molecular solids at ambient temperature. Single crystalline forms for an API (a) Pure API (b) Polymorph of pure API (c) Clathrate hydrate/solvate of API (d) Hydrate/solvate of API (e) Salt of API (f) Pharmaceutical cocrystal Salts and cocrystals can also form hydrates, solvates, and polymorphs Shan, J. and Zaworotko, J. Drug Discovery Today, 13, 440 (2008)

4 Pharmaceutical cocrystals Customize materials properties Melting point Stability Solubility Intrinsic dissolution bioavailability Technological point view Molecular level design of crystals with multiple components Develop large number of cocrystals for a given drug Commercial point view Enhanced product performance, controlled delivery IP protection Ning, Q., LI, M. et al. Int J Pharm, 419, 1, (2011)

5 Pharmaceutical cocrystals Solution mediated phase transformation : is crystallisation of a stable solid phase during dissolution of a metastable phase caused by supersaturated conditions in solution or at the surface of the dissolving solid. Davey and Cardew. J. Crys. Grow.,79, 648, (1986) Conversion occurs in three steps 1. Dissolution of a metastable phase 2. Nucleation of the stable phase 3. Growth of a stable phase Consequences 1. Reducing the dissolution rate 2. Dissolution rate gradually changes to that the stable crystalline form Advantages of the improved drug dissolution rate could be lost completely

6 Pharmaceutical cocrystals The purpose of this research was to gain a deep understanding of cocrystals Dissolution behaviour UV surface dissolution imaging Crystallisation behaviour Raman spectrometer

7 Model Drugs CBZ form III, CBZ form I, CBZ DH CBZ and NIC physical mixture 1:1 molar ratio CBZ- NIC cocrystal NH2 2 Amide to Amide structure Carboxamide groups from both CBZ and NIC provide hydrogen bonding donors and acceptors (a) CBZ (b) NIC (c) CBZ-NIC cocrystal Berry DJ. et al. Crys. Grow. Des. 8, 1697, (2008)

8 Cocrystal confirmation CBZ III FTIR DSC NIC С NIC CBZ-NIC cocrystal Compound Peak position (cm -1 ) Assignment Heat flow endo up CBZ III CBZ-NIC mixture CBZ-NIC cocrystal Raman Temperature ( o C) 175 С 128 С, 162 С 164 С CBZ III CBZ NH (C=O) NH 2 NIC 1695, (C=O) NH 2 of CBZ CBZ-NIC Cocrystal NH 2 of NIC (C=O)- of CBZ (C=O)- of NIC NIC CBZ-NIC mixture CBZ-NIC cocrystal

9 Monitoring of dissolution behaviour ActiPix SDI 300 UV surface imaging system (Paraytec Ltd., York, UK) 9mm 7µm 7µm Flow cell 7mm UV camera chip Syringe pump Ditemperature controller Single wavelength filter Focusing lens Sample surfaces Waste outlet Key features Real time monitoring of dissolution behaviour in flow through cell Tiny amounts of samples

10 Monitoring of dissolution behaviour UV imaging experimental conditions Dissolution medium: ph4.5 acetate buffer Temperature: 37+1 C Flow rate at 0.2ml/min Experimental protocol: set up the equipment and fill the system with buffer; program the UV imaging test method; drive bubbles out of the cartridge to get a clear imaging area; start the test program; after recording a dark image and reference image, pause recording and insert a sample compact; fill the Quartz dissolution cell with buffer (1ml/min) and make sure no bubbles in the cell or pipe, then start the pump programme (flow rate at 0.2ml/min) and resume the UV image recording. Each sample has been tested for 3 hours in triplicate.

11 Monitoring of dissolution behaviour CBZ DH 0 min 5 min 10 min 20 min 30 min Reference zone IDR measured zone Sample Contour line CBZ III 0 min 5 min 10 min 20 min 30 min CBZ I 0 min 5 min 10 min 20 min 30 min CBZ-NIC Cocrystal 0 min 5 min 10 min 20 min 30 min CBZ-NIC mixture 0 min 5 min 10 min 20 min 30 min

12 Monitoring of dissolution behaviour IDR (mg/min/cm2) IDRs as a function of dissolution time Time (min) CBZ III CBZ I CBZ DH Concentration decreases due to crystallisation of CBZ DH CBZ-NIC mixture CBZ-NIC cocrystal Within the first 3 minutes, all IDRs of the test samples reached its maximum values IDR of CBZ DH is almost constant IDR profiles of CBZ I and CBZ III are similar and maximum IDRs were obtained in 2 minutes and then decreased to relative stable values CBZ I has the IDR max of mg/min/cm 2 which declined to mg/min/cm 2 within 15 minutes Transition time of CBZ III is much slower than that of CBZ I, which took nearly 30 minutes The biggest variability of the IDR of CBZ- NIC mixture has been found, IDR profile of CBZ-NIC cocrystal is stable.

13 Monitoring of dissolution behaviour CBZ DH CBZ I CBZ III CBZ-NIC cocrystal CBZ-NIC mixture Before dissolution test After 3-hour dissoluti on test CBZ DH after CBZ III after CBZ I after CBZ-NIC cocrystal after CBZ-NIC mixture after CBZ DH before CBZ III before CBZ I before CBZ-NIC cocrystal before CBZ-NIC mixture before

14 Monitoring of dissolution behaviour All of test samples have undergone solution mediated phase transformations The transformation process happened rapidly for CBZ III, I, and physical mixture For CBZ-NIC cocrystal, the transition process is slow. The bonds of CBZ and NIC cocrystals can be maintained in the solution: delay phase transformation.

15 Monitoring of crystallisation behaviour Raman spectrometer Computer control Vertical adjust EnSpectr Raman Laser Sample in buffer Horizontal adjust Raman spectroscopy monitoring Dissolution medium: ph4.5 acetate buffer Room temperature Wavelength: 532 nm Spectral collection intervals: 5 minutes Experimental time: 3 hours

16 Monitoring of crystallisation behaviour No change CBZ DH CBZ I 180 min CBZ III 180 min 180 min 90 min 90 min 90 min 30 min 30 min 30 min 10 min 10 min 10 min 5 min 0 min CBZ-NIC mixture 5 min 0 min CBZ-NIC cocrystal 180 min 5 min 0 min 180 min 90 min 90 min 30 min 10 min 30 min 10 min Progression to CBZ DH 5 min 5 min 0 min 0 min

17 Monitoring of crystallisation behaviour Ratios of characteristic peaks Ratio of intensities 1035/ / /3025 begin finish begin finish begin finish CBZ DH 0.24± ± ±0.02 CBZ III 0.97± ±0.02 CBZ I 1.29± ±0.02 CBZ-NIC cocrystal 0.65± ±0.04 CBZ-NIC mixture 1.2± ±0.04 A first-order kinetics model to study the rate of conversion and the unconverted portion Y=B+Ae -kt K: is represented the rate of conversion Percentage of unconverted portion = (B-B DH )/ (B 0 -B DH ) B 0 is the ratio of characteristic peaks for the pure form of a sample and B DH is the ratio of characteristic peaks for the pure CBZ DH

18 Evolution of ratios characteristic peaks CBZ-NIC cocrystal CBZ-NIC physical mixture CBZ III CBZ I Rate constant (min -1 ) ± ± ± ± Unconverted portion (%) 7.83± ± ± ±2.33 IDR (mg/min/cm2) CBZ III CBZ I CBZ DH CBZ-NIC mixture CBZ-NIC cocrystal Time (min) Crystal growth rate

19 Conclusions UV imaging and Raman spectroscopy can provide in depth understanding during dissolution. The information on dynamic solublity and transformation behaviour of CBZ-NIC cocrystal is valuable for understanding the mechanisms of cocrystal dissolution, which helps to develop an in vitro-in vivo correlation for formulation development.

20 References Qiao N, Li M, Schlindwein W, Malek N, Davies A, Trappitt G. Pharmaceutical cocrystals: An overview. Int J Pharm. 2011;419(1-2):1-11. Qiao N, Wang N, Schlindwein W, Davies A, and Li M. In Situ Monitoring of Carbamazepine - Nicotinamide Cocrystal Intrinsic Dissolution Behaviour, submitted to EUR J PHARM BIOPHARM, 2012

21 Questions?