Investigation of Solid-state Stability of a Co-crystal API in Formulation Development by XRPD and ss- NMR Spectroscopy

Transcription

1 Investigation of Solid-state Stability of a Co-crystal API in Formulation Development by XRPD and ss- NMR Spectroscopy PPXRD-10 Lyon, France 17 May, 2011 Z. Jane Li, PhD Ph.D. Vincent Abeyta, Dabing Chen, Amar Khawam, Tom Offerdahl, Jung Park, John. Smoliga

2 This document was presented at PPXRD - Pharmaceutical Powder X-ray Diffraction Symposium Sponsored by The International Centre for Diffraction Data This presentation is provided by the International Centre for Diffraction Data in cooperation with the authors and presenters of the PPXRD symposia for the express purpose of educating the scientific community. All copyrights for the presentation are retained by the original authors. The ICDD has received permission from the authors to post this material on our website and make the material available for viewing. Usage is restricted for the purposes of education and scientific research. PPXRD Website ICDD Website -

3 Outline Introduction Multi-component API Solubility behavior Formulation development of a cocrystal API Cocrystal API physicochemical properties Initial i lformulation development Stability investigation New formulation effort Summary 2

4 Enhancing Drug Product Developability - In recent years, majority of drug candidates have poor solubility and slow dissolution BCS class II or IV - Solubility and dissolution limited exposure imposes significant challenge in achieving i clinical i l efficacy undesired physicochemical properties - Pressing needs to improve the efficiency of drug delivery, time and speed Manufacturability Processibility Scalability Stability Physical Chemical API Physicochemical Properties Performance Dissolution DP quality Efficacy - Most cost-effective and time-saving approach is to modify the API physicochemical properties salt/cocrystal 3

5 Co-crystallization Crystallization md + nx md a+ nx b- Dissolution m, n = 0; a, b = 0, fraction or integers (neutral or weak acid/base) A salt or a cocrystal contains two or more components Association by intermolecular interactions Salt - ions Stronger, direct Cocrystals - hydrogen bonding, or VdW interaction Mixed ionic and hydrogen bonding or partial proton transfer Crystalline API Weaker Multiple Salt - ionic ΔpKa continuum Cocrystal - non-ionic Proton transfer continuum 4

6 Advantage of Multi-component API ABCD Discovery safe and effective crystalline API without making/breaking covalent bonds.. Multi-component APIs allow tuning the properties p of drug substances to optimize developability of NCEs C. Aakeroy, KSU, 2009 Soluble guest molecule Modify intermolecular interactions and packing Limitations = Considerations 5

7 Solubility Behavior of Multi-component API Conc entration Time (hour) 1 is the free form Salts or cocrystals, 2,3, 4, can provide higher dissolution Factors: ph Particle size Additives surfactant, polymer Impurity Solvent composition Concentration Temperature Phase transformation Fluid dynamics stirring Apparatus Precipitation rate varies depending on many factors and may be controlled by selection of API or excipients Kinetic solubility complementary Equilibrium solubility 6

8 Formulation Development of Cocrystal API O S O H 2 N O OH N F F F F N H Molecular Weight = Molecular Formula = C 23 H 25 F 4 N 3 O 4 S Compound X is a weak base with a pka of ~3.9 initially by titration, possible for salts Projected high dose mg QD and low intrinsic solubility S o ~4 μg/ml, L predicted d a solubility limited i absorption 7

9 Solid Form Selection Six crystalline salts of compound X were isolated at the candidate nomination stage, only two were scalable, Salt 2 and Salt 3 Phosphate salt showed the most favorable physicochemical profile - Salt 2 is high melting, non-hygroscopic - Apparent solubility increased 50 fold compare to the FB - Bioavailability in rat showed a 4-fold improvement with suspension dosing - Dose was reduced by 10 fold - Physical and chemical stabilities were acceptable The pka of the parent compound was found to be 1.8 The single crystal structure of the phosphate salt revealed no proton transfer between the acid and the parent compound, thus, it is classified as a cocrystal 8

10 Comparison of Free Form and Cocrystal Parameter BS PH (24 hr) (2, 24 hours) Aqueous Solubility ph ph , 22 (µg/ml) ph ph , 12 ph ph , 10 Projected Human Dose (Allometry) mg/day mg / day (Phosphate) Dose Number , BCS II (using S 0 ) BCS II 8-20 (using S 2hr ) Crystallinity Crystalline Crystalline Melting Point (onset) = 226 C Melting Point (onset) = 203 C Thermal Behaviour Heat of Fusion = 100 J/g Heat of Fusion = 92 J/g Loss on Heating = 0.7% Loss on Heating = 0.4% Early Polymorph Screen Moderate Tendency No Indication to date Hygroscopicity, 80% RH % % Mouse (Suspension) = 41% Bioavailability Rat (Suspension) = 10% Dog (Suspension) = 5% Cyno (Suspension) = 4% Rat (Suspension) = 36-42% Cocrystal API of drug and PH enabled the candidate nomination 9

11 Crystal Structure of the Cocrystal Intramolecular H- bond No proton transfer PH Space group: P R1 = Cell dimention:8.33, 9.35, Data by H. Nar 10

12 Crystal Structure of the Cocrystal The drug molecule has 4 H-bond donors and 4 H-bond acceptors Phosphoric acid contains 3 H-bond donors and 4 H-bond acceptors Cocrystal structure No proton transfer from the acid to the drug molecule The acid forms a chain along the c axis 2 intra-molecular H-bonds; 9 inter-molecular H-bonds 11

13 Crystallinity and Morphology Cocrystal Lin (Counts) Free base Theta - Scale BI3048PH lot BI653048PHA07 initial - File: xr raw - Type: 2Th alone - Start: End: Step: Step time: 4. s - Temp.: 25 C (Room) - Time Started: 12 s - 2-Th Operations: Y Scale Add 7021 Import 3048BS lot# "As is" - File: xr raw - Type: 2Th alone - Start: End: Step: Step time: 4. s - Temp.: 25 C (Room) - Time Started: 12 s - 2-Theta: 3 Operations: Import 12

14 Solubility and Dissolution ty (ug/ml) BI BS Solubilit ph 1.18 = 20.4 μg/ml ph 1.95 = 7.20 μg/ml ph Phosphate is 15x faster than BS but relatively low, therefore may be still dissolution limited Total Releas sed (µg) Free base - Low solubility Free Base ph C Phosphate CoCrystal IDR = mg/min/cm 2 FB IDR = mg/min/cm Time (min) 13

15 In-Vitro and In-Vivo Correlation ABCD Dissolution Dissolution of BI of capsules BS H3PO4 filled with PIB and melt Gelucire granules Capsules, 90 mg (two-step dissolution, 100 ml SGF for 30 min. and 400 ml SIF for 60 min. paddle 50 rpm and then 250 rpm for 60 min at T=90 min.) % Dissolved 100 SGF SIF "D" 90 PIB 80 MCC/Manito E- MG "A" A- MG C - MG 20 "C" "B" 10 B- MG Cmax (nm) 10,500 6,940 4,970 3,510 2,170 In-Vitro and In-Vivo Correlation of BI BS H3PO4 (% dissolved at 10 min vs. Cmax) formulation "C" In vitro and in vivo correlation formulation "A" formulation "B" B- MG C A- MG PIB 1st PK study form. "D" Formulation "E" E- MG PIB Time (minutes) PIB control (n=2) 1st dog study form. "D" API/Gelucire/PEG 8000 (20:20:20%) melt gran.,xp (n=2), 1st dog study form. "A" API/Gelucire/PEG 8000 (40:20:20%), melt gran.,xp (n=2) 2), 1st dog study form. "B" % Disssolved at 10 min Formulations A, B, D and E provide a good in-vitro and in-vivo correlation with Cmax and AUC API/SDS/PEG 8000 (20:6:10%), wet gran., XP (n=1), 1st dog form. "C" API/TPGS/PEG 8000/PVP (20:25:10:5%), melt gran., XP (n=2) "E" Formulation E is selected for capsule formulation 14

16 Dissolution Profile of Stability Samples (Capsules) ABCD SGF SIF 1 month at 4C (HDPE bottle/induction seal) t = 0 Capsule filled with melt granules 80 % Dissolv ved month at 40C/75%RH (foil pouch) Cocrystal as DS is stable up to 40 o C month at 40C/75%RH (HDPE bottle/induction seal) Cocrystal in capsules is stable at 4 o C Time (minutes) BI304825mgcapsules capsules, 1Mat4C 4C, HDPEbottle bottle, XP (n=2) XP BI mg capsules, 1 M at 40C/75%RH, foil pouch, XP (n=2) Mannitol BI mg capsules, 1 M at 40C/75%RH, HDPE bottle, XP (n=2) BI mg capsules, t=0, (n=2) Cocrystal in capsules is not stable 15

17 Capsule Stability Mapping Solid Form Conversion Storage condition API phase 25 mg Capsules 2 25 o C/60% RH CC + FB 75 mg Capsules 2 40 o C/60% RH FB 2 4 o C CC 4M@ 4 o C CC + New o C CC 2 25 o C/60% RH CC + New 2M@ 4 o C CC Temp RH Time Drug loading Three solid phases of the drug in capsules CC, FB and an unknown (New) Temperature, relative humidity and time affected the rate of conversion 25 mg capsules showed faster rate of conversion, which were filled with same melt granules as 75mg but had larger head-space (moisture) 16

18 XRPD Patterns of Granules in Capsules Lin (Counts) XP , 25 C/60%RH (zero time) theta at 11 o is unique to FB XP , 40 C/75%RH (1 month) Theta - Scale It appears that cocrystal is converted to free base after storing 1month at 40 C/75%RH. 17

19 Phase Conversion in Formulation by 13 C ss-nmr The cocrystal 13 C Solid-state NMR The free base 25mg Capsules / 2M Stability 40C /75%RH Excipient Dissolution due to conversion from cocrystal to freebase In some samples, a new phase was detected 18

20 Excipients - Maintaining Supersaturation Effect of Excipient (5% w/v) 3000 l) Conc. (ug/m SDS PVP K-25 PEG 8000 Gelucire 50/13 MCC Time (hours) PEG 8000 (used in capsule formulation) and MCC cannot maintain supersaturation SDS is most effective in maintaining supersaturation The precipitate from PEG 8000 is the phase identified in ss-nmr in capsules 19

21 XRPD - Cocrystal and PEG and 17 2θ PEG 20% H3PO4 40/75 1d PEG 20% water 40/75 1d PEG wo water 40/75 1d 600 PEG cocrystal 20% water 25C 1 da PEG cocrystal physical mixture 0 tim PEG Theta - Scale New phase was confirmed by 13 C SS-NMR Excipients containing PEG chain also facilitated the conversion 20 Lin (Count ts)

22 13 C ss-nmr - Cocrystal and PEG 8000 Type J Freebase Cocrystal PEG+Cocrystal after storage 13 C SS-NMR spectrum of the mixture of PEG 8000 and CC after storage at 40 C/75% RH for one day 21

23 Dissolution of Wet Granulation % Dissolve ed 110 SGF SIF XP t=0 100 w/w% 90 rug BI XD SDS 6 80 PEG PVP 5 NaHPO H3PO Lactose MCC 15.2 Ac-Di-Sol 5 50 CSD 0.5 Mg. St t= 2wks 40C/75%RH, open Time (min) Wet granulation with PEG 8000 shows a significant drop on dissolution at 40 C/75%RH for 2 wks, open 22

24 Solid Form Conversion Map and Kinetics Cocrystal Anhydrate H 2 O Slurry Free base hydrate Metastable, only observed with API + PEG FB:A:PEG complex New phase Formation of PEG complex facilitated conversion to FB Free base Anhydrate High temp, drying, time Further study is ongoing 23

25 Storage Condition Moisture Effect ABCD Four tablet formulations were developed, using a combination of solubilizer and precipitation inhibitor. % Dissolved Tablet Dissolution Time (min) XP ,T=0,150mg 30C/30%RH,150mg tablets 30C/50%RH,150mg tablets 40C/50%RH,150mg tablets 40C/30%RH,150mg tablets Decrease in dissolution 50% RH (40 C) No 30% RH (40 C) Moisture induced phase transition minimizing moisture exposure by packaging with desiccant 24

26 Tablet Stability - Confirmation % D issolved SGF SIF initial 1 wk 40/75 open 70 w/w% 60 BI SDS PVP 10 KHSO H3PO Lactose MCC Ac-Di-Sol 5 CSD Mg. St Total Time (min.) 1 month 40 C/75%RH (open container) 1 week 40 C/75%RH (open container) Time zero After stored at 40 C/75%RH for1 month in open container, the wet granulation using a H3PO4 solution as a granulation agent is still a co-crystal which is confirmed by SSNMR 25

27 Cocrystal options Melting temp (C) Free base : 224 PH CC1: 203 NCTA CC2 : 191 Nicotinaminde tration ( μg/ml) Concent Time (min) BS 1 BS 2 H3PO4 CC 1 CC1 H3PO4 CC 2 Nic CC 1 CC2 Nic CC 2 Formation of cocrystals can modify physicochemical properties of the API which may offer alternative delivery profile 26

28 Summary - Cocrystal API The cocrystal of API improved dissolution rate significantly and enabled candidate nomination The cocrystal API showed excellent solid-state stability as API In an early formulation, a significant drop in dissolution was observed and attributed to the API phase conversion to the free base identified by XRPD and ss-nmr The conversion were induced by excipients PEG, and a combination of high humidity and high temperature Judicious selection of excipients and storage conditions prevented phase conversion and a stable tablet formulation was developed A combination of XRD and solid-state NMR techniques provided solid-state characterization in formulation 27

29 Acknowledgments Cocrystal selection and preparation Zhibin Li, Bing-shiou Yang Chao Tseng Soojin Kim Formulation development Peter Mayer George Gereg Doris Ciappetta Kathy Brigg Svetlana Sienkiewicz Lisa DeLattre Crystal structure Herbert Nar 28