Mechanistic investigation of Pluronic based nano-crystalline drug-polymer solid dispersions.
OBJECTIVE
To understand the mechanism of nano-crystalline drug formation in Pluronic (i.e., poly(ethylene oxide-block-propylene oxide) triblock copolymers) based drug-polymer solid dispersions.


METHODS
Four polymers, Pluronic F127, F108, F68 and PEG 8000, which have different poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO) ratio and chain length, were co-spray dried with BMS-347070, a COX-2 inhibitor, to form 50/50 (w/w) drug-polymer solid dispersions. The solid dispersions were analyzed by powder X-ray diffraction (PXRD), modulated differential scanning calorimetry (mDSC), and hot-stage microscopy. Average size of drug crystallites in different polymers was calculated by the Scherrer equation based on peak-broadening effect in PXRD. Two other drug compounds, BMS-A and BMS-B, were also spray dried with Pluronic F127, and the solid dispersions were analyzed by PXRD and mDSC.


RESULTS
The average size of BMS-347070 crystallites in PEG 8000, F127, F108 and F68 polymers was 69, 80, 98 and 136 nm, respectively, and the degree of BMS-347070 crystallinity is the lowest in PEG 8000. Hot-stage microscopy showed that 50/50 drug-polymer dispersions crystallized in a two-step process: a portion of the polymer crystallizes first (Step 1), followed by crystallization of drug and remaining polymer (Step 2). The T (g) value of the BMS-347070/Pluronic dispersions after Step 1 (i.e., T(g1)) was measured and/or calculated to be 15-26 degrees C, and that of BMS-347070/PEG 8000 was 60 degrees C. Solid dispersions of BMS-A and BMS-B in Pluronic F127 have T(g1) of 72 and 3 degrees C, respectively; and PXRD showed BMS-A remained amorphous after approximately 3 weeks under ambient condition, while BMS-B crystallized in F127 with an average crystallite size of 143 nm.


CONCLUSIONS
The size of drug crystallites in the drug-polymer solid dispersions is independent of polymer topology, but is caused kinetically by a combined effect of nucleation rate and crystal growth rate. When drug-Pluronic solid dispersions crystallize at room temperature, that is close to the T(g1) of the systems, a fast nucleation rate and a relatively slow crystal growth rate of the drug synergistically produced small crystallite size. While the much higher T(g1) value of drug-PEG 8000 led to a slower nucleation rate and an even slower crystal growth rate at room temperature, therefore, small crystallite size and low drug crystallinity were observed. Results from BMS-A/Pluronic and BMS-B/Pluronic systems confirmed this kinetic theory.
Qian
Feng
F
Biopharmaceutics R&D, Pharmaceutical Research Institute, Bristol-Myers Squibb Company, New Brunswick, New Jersey 08903, USA. feng.qian1@bms.com
Tao
Jing
J
Desikan
Sridhar
S
Hussain
Munir
M
Smith
Ronald L
RL
D002152:Calorimetry, Differential Scanning; D003460:Crystallization; D052246:Cyclooxygenase 2 Inhibitors / Q000737:chemistry; D005079:Excipients / Q000737:chemistry; D005663:Furans / Q000737:chemistry*; D007700:Kinetics; D008698:Mesylates / Q000737:chemistry*; D010316:Particle Size; D020442:Poloxamer / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry; D044366:Transition Temperature
D052246:Cyclooxygenase 2 Inhibitors; D005079:Excipients; D005663:Furans; D008698:Mesylates; C504079:(Z)-3-((4-bromophenyl)(4-(methylsulfonyl)phenyl)methylene)-4,5-dihydro-2(3H)-furanone; D020442:Poloxamer; D011092:Polyethylene Glycols