Nonlinear Optical Imaging for Sensitive Detection of Crystals in Bulk Amorphous Powders

Abstract

The primary aim of this study was to evaluate the utility of second-order nonlinear imaging of chiral crystals (SONICC) to quantify crystallinity in drug–polymer blends, including solid dispersions. Second harmonic generation (SHG) can potentially exhibit scaling with crystallinity between linear and quadratic depending on the nature of the source, and thus, it is important to determine the response of pharmaceutical powders. Physical mixtures containing different proportions of crystalline naproxen and hydroxyl propyl methyl cellulose acetate succinate (HPMCAS) were prepared by blending and a dispersion was produced by solvent evaporation. A custom-built SONICC instrument was used to characterize the SHG intensity as a function of the crystalline drug fraction in the various samples. Powder X-ray diffraction (PXRD) and Raman spectroscopy were used as complementary methods known to exhibit linear scaling. SONICC was able to detect crystalline drug even in the presence of 99.9 wt % HPMCAS in the binary mixtures. The calibration curve revealed a linear dynamic range with a R2 value of 0.99 spanning the range from 0.1 to 100 wt % naproxen with a root mean square error of prediction of 2.7%. Using the calibration curve, the errors in the validation samples were in the range of 5%–10%. Analysis of a 75 wt % HPMCAS–naproxen solid dispersion with SONICC revealed the presence of crystallites at an earlier time point than could be detected with PXRD and Raman spectroscopy. In addition, results from the crystallization kinetics experiment using SONICC were in good agreement with Raman spectroscopy and PXRD. In conclusion, SONICC has been found to be a sensitive technique for detecting low levels (0.1% or lower) of crystallinity, even in the presence of large quantities of a polymer.

Parts per Million Powder X-ray Diffraction

“…Previous studies of model systems have suggested detection limits on the order of ppm for crystallinity within amorphous solid dispersions. 28–32 …”

Drop printing of pharmaceuticals: Effect of molecular weight on PEG coated‐naproxen/PEG 3350 solid dispersions

“…23 It has recently been applied to quantify crystallinity without the need for any additional sample processing. 22,25 …”

Relevance of the Second Harmonic Generation to Characterize Crystalline Samples

“…First-order squaric acid [45] 2,3-dichloroquinizarin [46] HMX (octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine) [47] TATB (1,3,5-triamino-2,4,6-trinitrobenzene) [48] [(H 3 N(CH 2 )2SS(CH 2 )2NH 3 )PbI 5 ]ÁH 2 O [49] [C(NH2) 3 ]4Cl 2 SO 4 [50] (H 3 N(CH 2 ) 2 -S-S(CH 2 )2NH 3 )BiI 5 [51] 3-hydroxybenzoic acid [33,38] Orderdisorder triglycine sulfate [52] triazoyl ketone derivatives [53] P-SHG in-situ study of crystallization in a 390-mL stirring batch [54] quantification of structural and chemical purity [55,56] quantification of API in powdered and tableted samples [57] monitoring of pressure-induced transition [58] SHGM determination of the 3D orientation of organic nanocrystals embedded in a sol-gel matrix and distinction between monocrystalline and polycrystalline domains [59] determination of the degree of crystallinity in polymer mixtures; observation of the solid microstructure [60] detection of a metastable non-centrosymmetric polymorphic form in a chiral material; monitoring of nucleation and crystal growth; combination of several microscopic techniques [61,62] imaging of a pharmaceutical system involving several nonlinear optical processes [63] study of crystallinity and crystallization in an API/polymer mixture or in a pure API [64,65] selective imaging of API in powdered blends [66] crystallographic point group determination [67,68] study of growth-induced polarity formation [69] detection of a metastable non-centrosymmetric polymorphic form in a chiral material; confirmation of Ostwald's rule of stages; determination of the structural purity [70] development of SHGM at video rate [71] study of the organization of crystalline organic material inside an organic matrix [72] prediction of nonlinear optical responses from organic molecules [73,…”