Effect of RESS Process Parameters on Size Reduction of Drug Particles

1. Effect of RESS Process Parameters on Size Reduction of Drug Particles PRESENTED BY : RAMANI SUSARLA

2. INTRODUCTION In the pharmaceuticals industry, a large numbers of drugs are insoluble or poorly soluble in water. The bioavailability (the percentage of the drug absorbed compared to its initial dosage) is limited by this insolubility. The drug must first be dissolved in order to be absorbed. Dissolution rate is a function of the surface area of the particles and solubility. The surface area can be determined through the control of the particle size. Therefore, the bioavailability of the water insoluble drugs can be improved by reduction in their particle size (increase in surface area).

3. In the pharmaceutical industry, several conventional techniques have been utilized for particle size reduction such as crushing, grinding, milling, spray drying, freeze-drying, and recrystallization of the solute particles from solutions using liquid antisolvents. The disadvantages of using these conventional techniques are thermal and chemical degradation of products due to high temperatures, high energy requirements, large amounts of solvent use, solvent-disposal problems, solvent residues, and broad particle size distributions (PSDs).

4. In this respect, supercritical carbon dioxide shows its greatest advantage of ‘‘being environmentally benign’’; it can be used as a clean medium and thus potentially replace traditional solvents in many industrial processes. Besides, CO2 possesses low critical temperature and appreciable solubilising power for many organic compounds. Therefore carbon dioxide has been receiving increased attention in heat-sensitive and contaminant-free pharmaceutical processing. Currently, two common routes for particle formation in supercritical fluids are available: supercritical antisolvent processes and rapid expansion from supercritical solutions (RESS) . Supercritical CO2

5. RESS Process • The Rapid Expansion of Supercritical Solutions (RESS) is a supercritical fluid technology, which eliminates the drawbacks of the conventional micronization techniques to produce fine particles with narrow PSDs. • In the RESS process, the solute to be precipitated is first dissolved in the supercritical solvent, usually CO2, and then the supercritical solution is expanded through a fine diameter nozzle or capillary. The high supersaturation ratios (the ratio of the solute mole fraction at the extraction temperature and pressure to the equilibrium mole fraction value at the given temperature and pressure) and the homogeneous conditions attained due to the rapid expansion of a highly compressible supercritical mixture, are the distinguishing features of the RESS process. High supersaturation ratios lead the formation of small particles, and homogeneous conditions provide narrow PSD

6. RESS ADVANTAGES: With CO2 as a processing solvent, RESS can be conducted at a relatively low temperature where the thermal degradation of the drug and biopolymer is minimal, thus it has been employed for processing thermo-labile materials, like micronizing organic compounds and pharmaceuticals , fabricating polymer powders and fibers , and producing microencapsulations for drug delivery systems DISADVANTAGES: The main limitation of the RESS process is the low or no solubility of high molecular weight, polar compounds in non-toxic, non-flammable, and inexpensive CO2. In that case, the supercritical fluid may be used as an antisolvent for solid material.

7. Anti Solvent Processes The supercritical fluid technologies for producing fine particles in which supercritical solvent acts as an antisolvent, are Gas AntiSolvent recrystallization (GAS), Precipitation with a Compressed Antisolvent (PCA) and Supercritical AntiSolvent precipitation (SAS). In these antisolvent processes, the solute to be micronized is first dissolved in the liquid solvent. Then, the supercritical antisolvent, which is characterized by high diffusivities, is introduced into the liquid solution. The liquid solvent and the supercritical fluid are completely miscible. The addition of the supercritical antisolvent to the liquid solution causes a volume expansion in the liquid solvent, thus a decrease in its solvent strength, and provides supersaturation and precipitation of the solute.

8. RESS PROCESS CONDITIONS • The following process parameters which effect the size reduction are discussed: Extraction temperature, extraction pressure, pre-expansion temperature . Also discussed briefly are: Spray distance and contact angle. Three drug compounds have been discussed : Aspirin (Z.Huang et.al./ Powder Technology 160(2005) 127-134) Ibuprofen (D.Kayrak et.al./ Journal of Supercritical Fluids 26(2003) 17-31) salicylic acid (N.Yildiz et.al./ J.of Supercritical Fluids (2007)

9. Experimental Set-Up Z.Huang et.al./ Powder Technology 160(2005) 127-134

10. D.Kayrak et.al./ Journal of Supercritical Fluids 26(2003) 17-31

11. Aspirin

12. TABLE-2:Ibuprofen D.Kayrak et.al./ Journal of Supercritical Fluids 26(2003) 17-31

14. Effect of spraying distance: ibuprofen D.Kayrak et.al./ Journal of Supercritical Fluids 26(2003) 17-31

15. Effect of spray distance: salicylic acid N.Yildiz et.al./ J.of Supercritical Fluids (2007)

16. EFFECT OF EXTRACTION TEMPERATURE:ASPIRIN

18. Salicylic Acid

19. EFFECT OF EXTRACTION PRESSURE:ASPIRIN

20. Aspirin

21. EFFECT OF EXTRACTION PRESSURE:IBUPROFEN

22. Salicylic Acid

23. EFFECT OF PRE-EXPANSION TEMPERATURE • The effect of pre-expansion temperature on both ibuprofen and aspirin was found to be similar. It only resulted in slight decrease in the average particle size. • For ibuprofen an increase of approximatley 10 OC in the pre-expansion temperature in the range of 76-104 OC at an extraction pressure of 150 bar resulted only in a slight decrease in the particle size. • For aspirin the pre-expansion temperature was varied from 80-140 OC the effect on the particle size distribution was very less.

24. Effect of Pre-expansion Temperature: Salicylic acid

25. CHARECTERIZATION OF PROCESSED ASPIRIN AND IBUPROFEN:

26. XRD RESULTS:ASPIRIN

27. CONCLUSIONS • The effect of RESS process conditions on particle size morphology is evident. • RESS is an effective process for reduction of size particles. • It can be seen that the effect of pre-expansion temperature varied for aspirin, ibuprofen and salicylic acid. Based on these observations it can be said that the effect of parameters vary according to the drug compounds used. • A definite pattern of size reduction cannot be concluded in general, as the size reduction morphology changes for different drug particles.

28. REFERENCES • Nuray Yildiz, Sebnem Tuna, Onur Doker, Alya Calimli, The journal of supercritical fluids(2007). • Zhen Huang, Ge-Biao Sun, Yee C. Chiew, S.Kawi, Powder Technology 160(2005) 127-134. • Defne Kayrak, Ugur Akman, Oner Hortacsu, Journal of Supercritical Fluids 26(2003),17-31. • Ranjit Thakur, Ram B. Gupta, Journal of Supercritical Fluids 37(2006) 307-315.