Inverse gas chromatography a tool to follow physicochemical modifications of pharmaceutical solids: Crystal habit and particles size surface effects María Graciela Cares Pacheco, Rachel Calvet, G. Vaca-Medina, A. Rouilly, Fabienne Espitalier To cite this version: María Graciela Cares Pacheco, Rachel Calvet, G. Vaca-Medina, A. Rouilly, Fabienne Espitalier. In- verse gas chromatography a tool to follow physicochemical modifications of pharmaceutical solids: Crystal habit and particles size surface effects. International Journal of Pharmaceutics, Elsevier, 2015, 494 (1), pp.113-126. 10.1016/j.ijpharm.2015.07.078. hal-01611017 HAL Id: hal-01611017 https://hal.archives-ouvertes.fr/hal-01611017 Submitted on 5 Sep 2018 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Inverse gas chromatography a tool to follow physicochemical modifications of pharmaceutical solids: Crystal habit and particles size surface effects a, a b,c b,c a M.G. Cares-Pacheco *, R. Calvet , G. Vaca-Medina , A. Rouilly , F. Espitalier a Université de Toulouse; Mines Albi, UMR CNRS 5302, Centre RAPSODEE; Campus Jarlard, F-81013 Albi cedex 09, France b Université de Toulouse; INP-ENSIACET, LCA, 310130 Toulouse, France c INRA; UMR 1010 CAI, 310130 Toulouse, France A B S T R A C T Powders are complex systems and so pharmaceutical solids are not the exception. Nowadays, pharmaceutical ingredients must comply with well-defined draconian specifications imposing narrow particle size range, control on the mean particle size, crystalline structure, crystal habits aspect and surface properties of powders, among others. The different facets, physical forms, defects and/or impurities of the solid will alter its interaction properties. A powerful way of studying surface properties is based on the adsorption of an organic or water vapor on a powder. Inverse gas chromatography (IGC) appears as a useful method to characterize the surface properties of divided solids. The aim of this work is to study the sensitivity of IGC, in Henry’s domain, in order to detect the impact of size and morphology in surface energy of two crystalline forms of an excipient, D-mannitol. Surface energy analyses using IGC have shown that the a form is the most energetically active form. To study size and shape influence on polymorphism, pure a and b mannitol samples were cryomilled (CM) and/or spray dried (SD). All forms showed an increase of the surface energy after treatment, with a higher d 2 d 2 fl in uence for b samples (gs of 40–62 mJ mÀ ) than for a mannitol samples (gs of 75–86 mJ mÀ ). Surface 2 heterogeneity analysis in Henry’s domain showed a more heterogeneous b-CM sample (62–52 mJ mÀ ). Moreover, despite its spherical shape and quite homogeneous size distribution, b-SD mannitol samples 2 showed a slightly heterogeneous surface (57–52 mJ mÀ ) also higher than the recrystallized b pure 2 sample ( 40 mJ mÀ ). Keywords: D-mannitol Polymorphism Surface energy Inverse gas chromatography Spray drying Cryomilling 1. Introduction physical stability and crystallization behavior. The impact of these processes on solid phase transformations may lead to the Pharmaceutical solids must comply with well-defined speci- formation of a metastable or an amorphous form, or a mixtures fications in terms of bioavailability, solubility, toxicity and stability. of various crystalline forms including other hydrates (or solvates). Nowadays, the requirements are more and more draconian, These changes are desired for certain stages of the formulation or imposing narrow particle size range, control on the mean particle for some use properties of the API, but sometimes can also have size, crystalline structure, crystal habits aspect and surface undesirable effects on the solid. properties of powders, among others. A large set of operations Inverse gas chromatography (IGC) appears as a tool to study the is developed to answer these requirements. The processes for changes on surface properties in order to highlight process producing fine powders (around micrometer) are varied as melt influences to assess drug delivery systems performance. Mechani- quenching, grinding, freeze-drying, spray drying, crystallization, cal operations are the most studied processes to determine antisolvent precipitation, milling, and supercritical fluids. Depend- pharmaceutical solids surface’s behavior. Most authors described ing upon the nature of the active pharmaceutical ingredients an increase of the dispersive component of the solid surface d fl (APIs), it is known that the preparation method in uences the energy, gs , after mechanical grinding (Table 1). This increase is generally attributed to the exposure of specific crystal facets that present different chemical groups, the formation of higher energy zones such as crystal defects, dislocations and/or to solids state * Corresponding author. E-mail address: [email protected] (M.G. Cares-Pacheco). transformations (Chamarthy et Pinal, 2008; Feeley et al., 2002; Table 1 Nomenclature An overview of the influence of particles size reduction over the surface properties of pharmaceutical ingredients by IGC. 2 a (m /g) Specific surface area of the solid s d Pharmaceutical solid Reference gs d (n,0.5) (mm) Number median diameter Trowbridge et al. (1998) D [y,0.5] (mm) Median volume diameter Acetaminophen " Heng et al. (2006) Dgads (J/mol) Molar free energy variation for an isother- Cefditoren pivoxil Ohta and Buckton (2004) mal adsorption of probe molecules # DL-propanolol hydrochloride York et al. (1998) m (g) Sample mass " n Felodipine Chamarthy and Pinal (2008) (mol) Desorbed mole number " nads (mmol/g) Adsorbed mole number per gram of solid Chamarthy and Pinal (2008) nm (mol) Monolayer capacity or number of adsorbed Griseofulvine Feng et al. (2008) " moles corresponding to a monolayer Otte and Carvajal (2011) P (Pa) Vapor pressure or partial pressure Otte et al. (2012) # Psat (Pa) Saturation vapor pressure Ibipinabant Gamble et al. (2012) " T (K) Temperature Indomethacin Planinsek et al. (2010) Tc (K) Column temperature " Lim et al. (2013) Ahfat et al. (2000) tN (min) Net retention time 3 Feeley et al. (2002) VN (cm ) Net retention volume 2 Newell and Buckton (2004) W (J/m ) Work of adhesion when adsorption occurs Lactose adh Thielmann et al. (2007) " n/nm (–) Surface coverage Shariare et al. (2011) Brum and Burnett (2011) Jones et al. (2012) Greek symbols 2 d Mannitol Ho et al. (2012) gl (J/m or N/m) Liquid surface energy (or surface tension) " d 2 Salbutamol sulfate Ticehurst et al. (1994) gs (J/m or N/m) Dispersive component of solid surface Feeley et al. (1998) energy " 2 Tong et al. (2001, 2006) gs (J/m or N/m) Total surface energy of a solid Salmeterol Xinofoate sp 2 " Das et al. (2009) fi gs (J/m or N/m) Speci c component of solid surface energy Surana et al. (2003) Sucrose Hasegawa et al. (2009) us (–) Surface coverage " Luner et al. (2012) Succinic acid Luner et al. (2012) " Feng et al., 2008; Heng et al., 2006; Ho et al., 2012; Newell and are in agreement with those obtained by molecular modeling Buckton, 2004). which established that milling leads to the exposure of the crystal facet (0 10) which contain an hydrophobic methyl group, a 1.1. Surface energy, particles size and surface chemistry benzene ring and a carboxyl group, both basic. Ohta and Buckton (2004) studied surface energetic changes of Due to the anisotropic nature of powders, the exhibition of new cefditoren pivoxil, a cephalosporin antibiotic, as consequence of crystal faces under milling can change the acidic/basic character of milling. After grinding in a vibration mill, the authors found a the solid depending on the functional groups present in the d 2 decrease in the g according to the grinding time, from 52.3 mJ/m exposed facets. Heng et al. (2006) highlighted the anisotropic s 2 before milling to 45.8 mJ/m after 30 min of grinding with a nature of form I paracetamol crystals. The confrontation of sessile decrease in solid crystallinity. In addition, the authors have shown drop and IGC, allowed them to conclude that grinding leads to a a decrease in the solid acidic character with an increased on its fragmentation of the facet (0 10), which possesses the weakest d basicity. These effects are attributed to the exposure of carbonyl attachment energy and exhibits the large gs . Thus, after milling the d groups, which have an electron donating nature. gs of the samples increased, showing a more hydrophobic surface, Luner et al. (2012) studied by IGC the impact of high shear wet with decreasing particle size. milling (HSWM) and dry milling (DM) on the surface properties of York et al. (1998) were interested in the milling of DL- two pharmaceutical compounds, succinic acid and sucrose. d propranolol hydrochloride. The evolution of g showed to depend s Physicochemical characterization of both samples showed that on the particles size. During milling the surface becomes bulk properties were unaffected by wet and dry milling while d 2 increasingly more energetic (gs from 45 to 61 mJ/m for particles surface properties analyses showed an increase of solids dispersive d d – 75 16.5 mm) until reached a plateau followed by a small fall in gs surface energy after DM and HSWM. Succinic acid samples, gs 2 fi for the nest powder (<10 mm). The authors concluded that the = 35 mJ/m , exhibit minor differences between dry milled and wet d 2 increases in g , and in Dg using CH Cl as probe molecule, are milled samples, 40 2 mJ/m , attributed to minimal impact of s ads 2 2 Æ due to a fragmentation releasing the dominant crystal face, which cleavage and the exposure of crystal facets with similar atomic posses the lowest attachment energy and is rich in naphthalene surface arrangements.