Characterization of Newly Developed Micronized Poloxamers for Poorly Soluble Drugs

pharma SOLUTIONS Characterization of Newly Developed Micronized Poloxamers for Poorly Soluble Drugs n Actives n Excipients n Contract Manufacturing n Value Added Anisul Quadir, Ph.D, MBA Releasing Technology Workshops Controlled Release Society Meeting Miami, June 19, 2005 Helping make Pharmaceuticals betterTM Helping make Pharmaceuticals betterTM Poloxamers Chemical Nature Poloxamers are block-copolymers consisting of Polyoxyethylene-(POE-) and Polyoxypropylene-(POP-) units Chemical composition: CH HO CH 2 CH 2 O CH a POE-unit 3 CH 2 O CH b POP-unit CH 2 H O a POE-unit Pharmacopoeial name Poloxamer 188 Poloxamer 407 2 Trade Name a = ca. 79 a = ca. 98 n Actives Lutrol® F 68 Lutrol® F 127 b = ca. 28 b = ca. 57 n Excipients n Contract Manufacturing n Value Added Helping make Pharmaceuticals betterTM Lutrol® F Grades Brand Name n Lutrol F68NF n Lutrol F127NF Pharmacopeial Name n Poloxamer 188 n Poloxamer 407 Also Available n n n n Lutrol F87NF Lutrol L44NF Lutrol F108NF n n n Actives Poloxamer 237 Poloxamer 124 Poloxamer 338 n Excipients n Contract Manufacturing n Value Added Helping make Pharmaceuticals betterTM Poloxamers Characteristics The character of each poloxamer in terms of: n appearance n hydrophilicity / hydrophobicity n is determined by the chain length of the molecular weight n n polyoxyethylene(EO-) units solubility n Actives n Excipients AND n n polyoxypropylene(PO-) units Contract Manufacturing n Value Added Helping make Pharmaceuticals betterTM Poloxamer Grid Molecular weight of PO-part 4000 401 3625 402 Liquid Paste 334 333 331 3250 407 403 Solid 335 338 278 272 2750 221 2250 224 205 202 2050 182 183 184 122 181 1800 227 225 123 228 207 124 188 185 1450 1200 101 950 0 10 108 105 20 30 40 50 60 70 80 Percentage EO-part (%) n Actives n Excipients n Contract Manufacturing n Value Added Helping make Pharmaceuticals betterTM Poloxamer grades Definition of Number Code Mw of PO-part EO-part (Wt.%) Poloxamer 18 8 18 x 100 = 1800 8 x = 10 80 Poloxamer 40 7 40 x 100 = 4000 7 x = 10 70 n Actives n Excipients n Contract Manufacturing n Value Added Helping make Pharmaceuticals betterTM Lutrol® Grid 12000 11000 Molecular weight 10000 L121 Paste L101 P103 P104 Solid P105 F108 F98 L92 L81 P84 L61 L62 F87 P85 P75 L72 7000 6000 F127 P123 Liquid 9000 8000 L122 L63 L64 F88 F77 F68 P65 5000 4000 3000 0 L42 L43 L44 L31 10 F38 L35 20 30 40 50 60 70 80 Percentage EO-part (%) n Actives n Excipients n Contract Manufacturing n Value Added Helping make Pharmaceuticals betterTM Lutrol® F Grades Nomenclature Mw EO-part (Wt.%) Lutrol F 6 8 6 = x 1000 6000 8 x 10 = 80 Lutrol F 12 7 12 x 1000 = 12000 7 x 10 = 70 n Actives n Excipients n Contract Manufacturing n Value Added Helping make Pharmaceuticals betterTM Lutrol® F Grades Molecular Weight arbitr. units 5 lot-No. 89-0823 4,5 lot-No. 87-0807 4 3,5 3 2,5 2 1, 1 0,5 0 1.000 100 100.000 10.000 molecular weight Lutrol F 68 lot-No. 89-0823 lot-No. 87-0807 Mw 8,600 9,000 n Actives Mn 7,600 8,100 n Excipients (Mw/Mn) 1.4 1.4 n Contract Manufacturing n Value Added Helping make Pharmaceuticals betterTM Lutrol® F127 Molecular Weight arbitr. units 5 4,5 4 3,5 3 2,5 2 1, 5 1 0,5 0 1.000 100 10.000 100.000 molecular weight Lutrol F 127 lot-No. 41-0805 lot-No. 64-0806 Mw Mn 13,400 13,500 n Actives (Mw/Mn) 1.4 1.4 9300 9500 n Excipients n Contract Manufacturing n Value Added Helping make Pharmaceuticals betterTM Lutrol F127 Reason for Bimodal Distribution n The molecular weight distribution is dependant on side reactions, which occur during propylene oxide polymerization. n During formation of POP block, a fraction of propylene oxide may be converted to allyl alcohol which will futher react with PO and EO producing a polymeric material about half the molecular weight of the main product. This segment constitute the unsaturation part of Lutrol F127 ( 0.048 meq/gm). n In the USP, the average molecular weight is 9840 to 14600. n Actives n Excipients n Contract Manufacturing n Value Added Helping make Pharmaceuticals betterTM Formation of Unsaturation H H O O KOH K + H H H O H n+1 O H H CH 2 CHO O CH 3 n K Unsat. in USP/NF for 407 = 0.048 + 0.017 mEq/g + m O O CH 2 CHO n CH 2 CH 2 O m H CH 3 n Actives n Excipients CONFIDENTIAL n Contract Manufacturing n Value Added Helping make Pharmaceuticals betterTM Functionality of Poloxamer 407 CH3 HO-(CH2-CH2-O)x-(CH2-CH-O)y-(CH2-CH2-O)x-H where x = approx. 98 and y = approx. 57 Poloxamer is terminated with hydroxyl group therefore further reactions will not occur (will not self polymerize) n Actives n Excipients n Contract Manufacturing n Value Added Helping make Pharmaceuticals betterTM Principle of Micellization surfactant m o lecule Polar Solvent n Actives n Excipients n Contract Manufacturing n Value Added Helping make Pharmaceuticals betterTM As a Solubilizer Solubilization capacity of a poloxamer is believed to be dictated by the hydrophobic portion One theory is that in water, the poloxamer molecules arrange themselves in an “umbrella” like configuration: One Poloxamer molecule POP Group POE Group n Actives n Excipients n Contract Manufacturing n Value Added Helping make Pharmaceuticals betterTM Limiting Aggregation Concentration From the available literature: • Poloxamer 188 (Lutrol F 68) 6.0 micromoles/ liter •Poloxamer 338 (Lutrol F 108) 4.74 micromoles/ liter •Poloxamer 407 (Lutrol F 127)* 2-3 micromoles/liter * Estimated, no published literature. n Actives n Excipients n Contract Manufacturing n Value Added Helping make Pharmaceuticals betterTM Lutrol® F Grades Applications Solubilizer Solubilizer Gels Gels Suspension Suspension Stabilizer Stabilizer Melt //Spray Melt Spray Granulations Granulations n Actives n Excipients n Contract Manufacturing n Value Added Helping make Pharmaceuticals betterTM Lutrol® F Grades (Poloxamers) Prill Microprill n Lutrol F68 Prill n Lutrol 68*micro n Lutrol F127 Prill n Lutrol 127* micro n Particle Size Range n n n n Actives n d (0.5) = 50micron d (0.9) = 90 micron *Development Product Excipients n Contract Manufacturing n Value Added Helping make Pharmaceuticals betterTM Advantages of Microprilling n Average particle size 50 micron n Stronger solubilization activities n Controlled dissolution rate n Reduction of die-wall friction n Achievement of homogeneous blend n Elimination of dose dumping n Effective water soluble lubricant n Actives n Excipients n Contract Manufacturing n Value Added Helping make Pharmaceuticals betterTM Microprill Lutrol® Particle Size Specification Microprill meets the following specification n Max. 10% retain in 106 micron (#140 Screen) n Max. 50% retain on 53 micron (#270 Screen) n Using Alpine Air Jet Sieve Analysis n Chemical Specification is identical to regular prill and complies with USP/NF specification n Actives n Excipients n Contract Manufacturing n Value Added Helping make Pharmaceuticals betterTM SEM Lutrol® F68 Prill x50 magnification Lutrol® 68 Microprill x500 magnification n Actives n Excipients n Contract Manufacturing n Value Added Helping make Pharmaceuticals betterTM Particle Size Using Malvern Mastersizer 2000 Lutrol® F68 Prill Lutrol® 68 Microprill Particle Size Distribution Particle Size Distribution 13 100 12 11 90 10 80 70 Volume (%) Volume (%) 9 8 60 7 6 50 5 40 4 30 3 20 2 10 1 0 0.1 1 10 Particle Size (µm) 100 1000 0 3000 10 9.5 9 8.5 8 7.5 7 6.5 6 5.5 5 4.5 4 3.5 3 2.5 2 1.5 1 0.5 0 0.1 100 90 80 70 60 50 40 30 20 10 1 10 Particle Size (µm) 100 1000 0 3000 F68 microprilled, WPNZ-664BMP Averaged Result, 08/06/04 11:33:33 F68 Prill, sifted, WPOZ-551BK4 Averaged Result, 08/06/04 11:25:51 n Actives n Excipients n Contract Manufacturing n Value Added Helping make Pharmaceuticals betterTM Surface Area BET Surface (m2/g) Sample Lutrol® F68 Lot # 55-0003 Not Possible Lutrol® 68 Microprill Lot # WPNZ-664BMP n Actives 0.18 n Excipients n Contract Manufacturing n Value Added Helping make Pharmaceuticals betterTM Bulk / Tapped Density Bulk Density (g/cm3) Tapped Density (g/cm3) True Density (g/cm3) Lutrol® F68 Prill Lot # WPDX-577B 0.56 0.60 0.99 Lutrol® 68 Microprill Lot # WPNZ-664BMP 0.52 0.78 1.10 Material n Actives n Excipients n Contract Manufacturing n Value Added Helping make Pharmaceuticals betterTM Melt Viscosity Viscosity (cps) F68 Prill 68 Microprill Initial 807 730 Stabilized 783 720 Equipment : Brookfield RVT-DVII with Thermoseal & Temperature Controller Temperature Set and Maintained at 80°C, Spindle #27 n Actives n Excipients n Contract Manufacturing n Value Added Helping make Pharmaceuticals betterTM Molecular Weight Distribution (GPC) - Sample Name 1 Mn MP 8611 9332 9956 1.083755 100.0 2861502 18.411 2S011 8809 Lutrol® F68 Microprill WPNZ-664BMP Mw Polydispersity % Area Area Retention Time Project # 9656 10288 1.096190 100.0 3711903 18.356 2S011 (microprill) Date Acquired 10/18/04 9:05:37 AM 2 Lutrol® F68 Prill – WPOZ-551BK4 (normal prill) Date Acquired 10/18/04 10:45:31 AM 15.00 16.00 17.00 18.00 19.00 20.00 21.00 n Actives 22.00 23.00 Minutes n 24.00 Excipients 25.00 26.00 n 27.00 28.00 29.00 Contract Manufacturing 30.00 n Value Added Helping make Pharmaceuticals betterTM Differential Scanning Calorimetric Data To Tp ∆H Lutrol® F68 Prill 48.9 51.6 121.7 Lutrol® 68 Microprill 50.1 52.4 121.7 Material To = Extrapoloated onset of melting endotherm in °C Tp = Peak of melting endotherm in °C ∆H = Enthalpy of melting endotherm in joules/gram n Actives n Excipients n Contract Manufacturing n Value Added Helping make Pharmaceuticals betterTM DSC Lutrol® F68 Prill Run DSC : 2 Heat Flow (W/g) 2nd heat 50.09°C 134.3J/g 0 -2 - -4 - 53.56°C Exo Up Lutrol® 68 Microprill -40 -20 0 20 40 60 80 100 Universal V3.8B TA Instruments Temperature (°C) DSC 2 Heat Flow (W/g) -6 -60 2nd heat 1 2°C/min 49.64°C 119.8J/g 0 -1 52.32°C -2 0 Exo Up n Actives n Excipients 10 20 n 30 40 50 60 Temperature (°C) Contract Manufacturing 70 80 n 90 100 Value Added Helping make Pharmaceuticals betterTM X-Ray Diffraction 14000 13000 12000 n Lutrol® F68 Prill 11000 n Lutrol® 68 Microprill 10000 9000 Lin 8000 (Co unt 7000 s) 6000 5000 4000 3000 2000 1000 0 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 2-Theta - Scale - - - - - - - - -2 - - - - - - - - - - - - - - - ° n Actives n Excipients n -° - -° - - - -° -. Contract Manufacturing n Value Added pharma SOLUTIONS Case Study – Effects of micronized poloxamers on poorly water soluble drugs n Actives n Excipients n Contract Manufacturing n Value Added Helping make Pharmaceuticals betterTM Helping make Pharmaceuticals betterTM Formulations Material Formulation A (%) Formulation B (%) Ibuprofen 5.0 - - 5.0 5.0, 25.0, 50.0 25.0, 50.0 79.0, 69.0, 59.0, 34.0 - - 59.0, 34.0 Kollidon CL 10.0 10.0 Aerosil 200 0.5 0.5 Magnesium Stearate 0.5 0.5 Carbamazepine Lµtrol micro® Di-calcium Phosphate Calcium Carbonate 90A n Actives n Excipients n Contract Manufacturing n Value Added Helping make Pharmaceuticals betterTM Ibuprofen Capsule Data Capsules containing Ibuprofen and Lutrol® 127 Micro 90 80 % Drug Release 70 60 50 40 1:1 Ratio 30 1:5 Ratio 20 1:10 Ratio 10 Control 0 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 Time (Hrs) Dissolution Media pH 4.5 buffer HPLC Column 5µm C18 150mm x 39mm n Actives n Excipients Mobile Phase: H20:Acetonitrile (40:60) n Contract Manufacturing n Value Added Helping make Pharmaceuticals betterTM Ibuprofen Tablet Data Tablets containing Ibuprofen and Lutrol ® 127 Micro 120 % Drug Release 100 80 60 40 1:1 Ratio 1:5 Ratio 20 1:10 Ratio Control 0 0 1 2 3 4 5 Time (hrs) Dissolution Media pH 4.5 buffer HPLC Column 5µm C18 150mm x 39mm n Actives n Excipients Mobile Phase: H20:Acetonitrile (40:60) n Contract Manufacturing n Value Added Helping make Pharmaceuticals betterTM Ibuprofen and Lutrol® F127 Prill vs. Micro grades (1:10) Ibuprofen tablets containing Lutrol 127 Prill and Micro grades 120 % Drug Release 100 80 60 40 Lutrol 127 micro 20 Lutrol F127 Prill 0 0 1 2 3 4 5 Time (hrs) Dissolution Media pH 4.5 buffer HPLC Column 5µm C18 150mm x 39mm n Actives n Excipients Mobile Phase: H20:Acetonitrile (40:60) n Contract Manufacturing n Value Added Helping make Pharmaceuticals betterTM Conclusion For Ibuprofen n The addition of Lutrol® 127 micro improved the dissolution of Ibuprofen n Tablets showed a greater improvement in dissolution compared to capsules n The thermoreversible gelling effect, along with the smaller particle size of Lutrol 127 micro gave a controlled release profile n Actives n Excipients n Contract Manufacturing n Value Added Helping make Pharmaceuticals betterTM Carbamazepine Formulations Process n Dissolution studies with tablets via direct compression and solid dispersion were evaluated n Regular prill used for Solid dispersion and Microprill for Direct Compression n Tablets compressed using 9.5mm round flat face bevel edge tooling n Target weight 400mg, target hardness 4-5Kp n Using Carbamazepine as a model drug, due to its limited solubility in water – dissolution studies were carried out using a co-solvent of water and ethanol (70:30) n Actives n Excipients n Contract Manufacturing n Value Added Helping make Pharmaceuticals betterTM Carbamazepine and Lutrol® 127 1:5 ratio Carbamazepine and Lutrol 127 micro 1:5 Ratio 90 80 % Drug Release 70 60 50 40 30 Direct Compression 20 Solid Dispersion 10 Control 0 0 1 2 3 4 5 Time (hrs) Dissolution Media 70:30 Ethanol:Water HPLC Column 5µm CN 250mm x 4.6mm n Actives n Excipients n Mobile Phase: H20:MeOH:THF (85:12:3) Contract Manufacturing n Value Added Helping make Pharmaceuticals betterTM Carbamazepine and Lutrol® 127 1:10 ratio Carbamazepine and Lutrol 127 micro 1:10 Ratio 90 80 % Drug Release 70 60 50 40 30 Solid Dispersion 20 Direct Compression 10 Control 0 0 1 2 3 4 5 Time (Hrs) Dissolution Media 70:30 Ethanol:Water HPLC Column 5µm CN 250mm x 4.6mm n Actives n Excipients n Mobile Phase: H20:MeOH:THF (85:12:3) Contract Manufacturing n Value Added Helping make Pharmaceuticals betterTM Carbamazepine and Lutrol® 68 1:5 ratio Carbamazepine and Lutrol 68 micro 1:5 Ratio 90 80 % Drug Release 70 60 50 40 30 Solid Dispersion 20 Direct Compression 10 Control 0 0 1 2 3 4 5 Time (Hrs) Dissolution Media 70:30 Ethanol:Water HPLC Column 5µm CN 250mm x 4.6mm n Actives n Excipients n Mobile Phase: H20:MeOH:THF (85:12:3) Contract Manufacturing n Value Added Helping make Pharmaceuticals betterTM Carbamazepine and Lutrol® 68 1:10 ratio Carbamazepine and Lutrol 68 micro 1:10 Ratio 120 % Drug Release 100 80 60 40 Solid Dispersion Direct Compression 20 Control 0 0 1 2 3 4 5 Time (hrs) Dissolution Media 70:30 Ethanol:Water HPLC Column 5µm CN 250mm x 4.6mm n Actives n Excipients n Mobile Phase: H20:MeOH:THF (85:12:3) Contract Manufacturing n Value Added Helping make Pharmaceuticals betterTM Conclusions For Carbamazepine n Both Lutrol® 68 micro and Lutrol 127 micro improved the dissolution of Carbamazepine n Solid dispersion techniques appeared to provide incomplete release of Carbamazepine n Actives n Excipients n Contract Manufacturing n Value Added pharma SOLUTIONS Case Study 2 Comparing different granulation techniques n Actives n Excipients n Contract Manufacturing n Value Added Helping make Pharmaceuticals betterTM Helping make Pharmaceuticals betterTM Formulation and Process n Made Carbamazepine tablets using different granulation techniques: n Direct Compression n Wet Granulation n Melt Granulation n n Two ratios evaluated: 1:3 and 1:5 (Drug: Poloxamer) Microprill was used only in Direct Compression n Tablets compressed at 400mg, target hardness 5-7Kp n Actives n Excipients n Contract Manufacturing n Value Added Helping make Pharmaceuticals betterTM Lutrol® 68 micro 1:3 Ratio Carbamazepine and Lutrol F 68 1:3 Ratio 120 % Drug Release 100 80 60 Direct Compression 40 Melt Granulation Wet Granulation 20 Control 0 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 Time (Mins) n Actives n Excipients n Contract Manufacturing n Value Added Helping make Pharmaceuticals betterTM Lutrol® 68 micro 1:5 ratio Carbamazepine and Lutrol 68 1:5 Ratio 100 90 80 % Drug Release 70 60 50 40 Direct Compression 30 Melt Granulation 20 Wet Granulation 10 Control 0 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 Time (Hrs) n Actives n Excipients n Contract Manufacturing n Value Added Helping make Pharmaceuticals betterTM Lutrol® 127 micro 1:3 ratio Carbamazepine and Lutrol 127 1:3 Ratio 120 % Drug Release 100 80 60 Direct Compression 40 Melt Granulation Wet Granulation 20 Control 0 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 Time (Hrs) n Actives n Excipients n Contract Manufacturing n Value Added Helping make Pharmaceuticals betterTM Lutrol® 127 micro 1:5 ratio Carbamazepine and Lutrol 127 1:5 Ratio 120 % Drug Release 100 80 60 Direct Compression 40 Wet Granulation Melt Granulation 20 Control 0 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 Time (Hrs) n Actives n Excipients n Contract Manufacturing n Value Added Helping make Pharmaceuticals betterTM Lutrol® 127 micro Dissolution Comparing 1:5 and 1:3 ratio Lutrol 127 direct compression tablet 90 80 % Drug Release 70 60 50 40 30 20 1:5 Ratio Lutrol 127 10 1:3 Ratio Lutrol 127 0 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 Time (Hrs) n Actives n Excipients n Contract Manufacturing n Value Added Helping make Pharmaceuticals betterTM Conclusions n Use of poloxamers, regardless of granulation technique, improved the solubility of Carbamazepine. n Higher levels of poloxamer create a greater binding effect, which has an impact on dissolution. n Microprilled Poloxamers exhibit good blend homogeneity and eliminate the segregation problem during direct compression. n The gelling characteristic of microprilled Poloxamer 407 can be used for controlled release or other drug delivery technology. n Microprill poloxamer can be a good candidate as a water soluble lubricant for effervescent tablets. n Actives n Excipients n Contract Manufacturing n Value Added Helping make Pharmaceuticals betterTM ARE THERE ANY QUESTIONS ???? n Actives n Excipients n Contract Manufacturing n Value Added Helping make Pharmaceuticals betterTM Ibuprofen Formulations Process n Dissolution studies with capsules and tablets were evaluated n Tablets compressed using 11mm round flat face bevel edge tooling n Target weight 800mg, target hardness 4-5Kp n Using Ibuprofen as a model drug – dissolution studies were carried out at pH 4.5 (where Ibuprofen has limited solubility) n n Actives CRS 2005/ 32nd Symposium on Controlled Release of Bioactive Materials / 18.-22.06.2005 / Miami, Florida, U.S.A. n Excipients n Contract Manufacturing n Value Added