Amorphization of Indomethacin by Co-Grinding with Neusilin US2: Amorphization Kinetics, Physical Stability and Mechanism

PurposeTo quantify the effects of the ratio of indomethacin to Neusilin US2 and the processing humidity on the amorphization kinetics, stability and nature of the interaction.Materials and MethodsA porcelain jar mill with zirconia balls was used to affect conversion of the physical mixtures (48 g) of indomethacin and Neusilin US2 (in the ratios 1:1 to 1:5) to amorphous states at room temperature (25°C) employing either 0% RH or 75% RH. The percent crystallinity in the samples was determined from ATR-FTIR scans chemometrically. The physical stability of these co-ground amorphous powders was evaluated at 40°C/75% RH and 40°C/0% RH.ResultsThe lower the ratio of indomethacin to Neusilin US2, the faster is the amorphization during co-grinding. Higher humidity facilitates amorphization with a more pronounced effect at the lower ratio of indomethacin to Neusilin US2. There is further amorphization of some of the partially amorphized samples on storage at 40°C/75% RH for 3 months. Hydrogen bonding and surface interaction between metal ions of Neusilin US2 and indomethacin can explain changes in the FTIR spectra.ConclusionsThe processing humidity and the ratio of indomethacin to Neusilin US2 are important factors to be considered to affect amorphization during ball milling. Amorphous indomethacin can be stabilized by co-grinding with Neusilin US2.

[1]  A. Jubert,et al.  Vibrational and theoretical studies of the non-steroidal anti-inflamatory drugs Niflumic [2-3((3-trifluoromethyl)phenylamino)-3-pyridinecarboxylic acid]; Diclofenac [[2-(2,6-dichlorophenyl)amino]-benzeneacetic acid] and Indometacin acids [1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic aci , 2005 .

[2]  C. Jarowski,et al.  Effects of amorphous silicon dioxides on drug dissolution. , 1979, Journal of pharmaceutical sciences.

[3]  T. Konno,et al.  Physical and chemical changes of medicinals in mixtures with adsorbents in the solid state. I. Effect of vapor pressure of the medicinals on changes in crystalline properties. , 1986, Chemical & pharmaceutical bulletin.

[4]  G. Maciel,et al.  PROBING HYDROGEN BONDING AND THE LOCAL ENVIRONMENT OF SILANOLS ON SILICA SURFACES VIA NUCLEAR SPIN CROSS POLARIZATION DYNAMICS , 1996 .

[5]  A. Ikekawa,et al.  Solubilization of Water-Insoluble Organic Powders by Ball-Milling in the Presence of Polyvinylpyrrolidone , 1975 .

[6]  Hirofumi Takeuchi,et al.  Solid dispersion particles of amorphous indomethacin with fine porous silica particles by using spray-drying method. , 2005, International journal of pharmaceutics.

[7]  Manish K. Gupta,et al.  Hydrogen Bonding with Adsorbent During Storage Governs Drug Dissolution from Solid-Dispersion Granules , 2002, Pharmaceutical Research.

[8]  Lynne S. Taylor,et al.  Spectroscopic Characterization of Interactions Between PVP and Indomethacin in Amorphous Molecular Dispersions , 1997, Pharmaceutical Research.

[9]  K. H. Kim,et al.  Application of differential scanning calorimetry to the study of solid drug dispersions. , 1985, Journal of pharmaceutical sciences.

[10]  A. Politov,et al.  The mechanochemical preparation of solid disperse systems of ibuprofen-polyethylene glycol , 1996 .

[11]  E. Fukuoka,et al.  Effect of Grinding on Physical and Chemical Properties of Crystalline Medicinals with Microcrystalline Cellulose. II. : Retention of Volatile Medicinals in Ground Mixture , 1978 .

[12]  A. Ikekawa,et al.  A decrease in crystallinity of amobarbital by mechanical treatment in the presence of the diluents. , 1978 .

[13]  M Ikeda,et al.  Stability of amorphous indomethacin compounded with silica. , 2001, International journal of pharmaceutics.

[14]  G. Maciel,et al.  A Detailed Model of Local Structure and Silanol Hydrogen Bonding of Silica Gel Surfaces , 1997 .

[15]  R. Bogner,et al.  Formation of physically stable amorphous drugs by milling with Neusilin. , 2003, Journal of pharmaceutical sciences.

[16]  G Zografi,et al.  How does residual water affect the solid-state degradation of drugs in the amorphous state? , 1996, Journal of pharmaceutical sciences.

[17]  George Zografi,et al.  The Molecular Mobility of Supercooled Amorphous Indomethacin as a Function of Temperature and Relative Humidity , 1998, Pharmaceutical Research.

[18]  M. Kinoshita,et al.  Improvement of solubility and oral bioavailability of a poorly water-soluble drug, TAS-301, by its melt-adsorption on a porous calcium silicate. , 2002, Journal of pharmaceutical sciences.

[19]  H. Sunada,et al.  Solid-State Interaction of Ibuprofen with Polyvinylpyrrolidone , 1995 .

[20]  S. Furlanetto,et al.  Solid-state characterization of glyburide-cyclodextrin co-ground products , 2004 .

[21]  G Zografi,et al.  A study of amorphous molecular dispersions of indomethacin and its sodium salt. , 2001, Journal of pharmaceutical sciences.

[22]  G. Zografi,et al.  Water vapor absorption into amorphous hydrophobic drug/poly(vinylpyrrolidone) dispersions. , 2002, Journal of pharmaceutical sciences.

[23]  E. Yonemochi,et al.  Improved Dissolution of Naproxen from Solid Dispersions with Porous Additives , 1997 .

[24]  George Zografi,et al.  Solid-State Characteristics of Amorphous Sodium Indomethacin Relative to Its Free Acid , 1999, Pharmaceutical Research.

[25]  M. Fujii,et al.  Preparation, characterization, and tableting of a solid dispersion of indomethacin with crospovidone. , 2005, International journal of pharmaceutics.

[26]  V. Boldyrev,et al.  Preparation of the Disperse Systems of Sulfathiazole-Polyvinylpyhrolidone by Mechanical Activation , 1994 .

[27]  M. Senna,et al.  Comparison between polyvinylpyrrolidone and silica nanoparticles as carriers for indomethacin in a solid state dispersion. , 2003, International journal of pharmaceutics.

[28]  P. Mura,et al.  Investigation of the effects of grinding and co-grinding on physicochemical properties of glisentide. , 2002, Journal of pharmaceutical and biomedical analysis.

[29]  R. Bogner,et al.  Mechanism for Further Enhancement in Drug Dissolution from Solid-Dispersion Granules upon Storage , 2002, Pharmaceutical development and technology.

[30]  M. Senna,et al.  Prediction of apparent equilibrium solubility of indomethacin compounded with silica by 13C solid state NMR. , 2002, International journal of pharmaceutics.

[31]  Bruno C. Hancock,et al.  What is the True Solubility Advantage for Amorphous Pharmaceuticals? , 2000, Pharmaceutical Research.

[32]  E. Fukuoka,et al.  Effects of grinding on physical and chemical properties of crystalline medicinals with microcrystalline cellulose. I. Some physical properties of crystalline medicinals in ground mixtures. , 1977, Chemical & pharmaceutical bulletin.

[33]  Cheng Gu,et al.  Interaction of tetracycline with aluminum and iron hydrous oxides. , 2005, Environmental science & technology.

[34]  S. Byrn.  Solid state chemistry of drugs , 1982 .

[35]  Ahmed S. Ali,et al.  Molecular Behavior of Flufenamic Acid in Physical and Ground Mixtures with Florite , 1992 .

[36]  E. Yonemochi,et al.  Physicochemical properties of amorphous clarithromycin obtained by grinding and spray drying. , 1999, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.