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RAMAN


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Authors Pautot et al.


Kennedy et al. Kang et al. Kang et al. Kang et al. Meyer et al.


Windbergs et al. Jurna et al.


Day et al.


Slipchenko et al. Wanapun et al.


Wanapun et al. Toth et al.


Wang et al. Kestur et al.


Hsu et al. Garbacik et al. Fussell et al.


Year Techniques Samples 2003 2005


CARS CARS


2006 2007 2008 2008 2009 2010


2010 2010


2011 2012


2012 2012


2013 2013


2013 CARS CARS CARS CARS CARS CARS


SRS and CARS SHG


SHG TPEF and SHG


SRS SHG


SHG CARS CARS


Table 1. Some publications for nonlinear optical imaging of pharmaceutical formulations Conclusions


Dodecane emulsions Surfactant in myelin fi gures Paclitaxel loaded polymer fi lms Paclitaxel loaded polymer fi lms Paclitaxel loaded polymer fi lms Multiple emulsions


Theophylline containing tablets and lipid extrudates


Oil-in-water emulsions Commercial Amlodipine tablets CARS capable of imaging variation in composition of emulsions


CARS used to map the molecular composition and orientation inside myelin fi gures


CARS microscopy eff ective for imaging native drug molecules in polymer matrices


CARS microscopy showed that drug release from polymer matrix is closely related with its distribution


CARS was useful in studying drug release from polymer fi lms without drug labeling


CARS could image spatial distribution of components within single emulsion droplets with submicrometer resolution


CARS used to visualize spatial distribution of diff erent components in oral pharmaceutical dosage forms and drug release during dissolution


CARS used to discriminate between undigested oil and lipolytic products without labeling


SRS allows selective imaging of drug molecules and excipients


Amorphous griseofulvin and chlorpropamide SHG used to sensitively and selectively detect existence and formation of crystalline APIs


Amorphous griseofulvin


Griseofulvin, various excipients, commercial tadalafi l tablet


Griseofulvin loaded HPMC fi lms Naproxen-HPMCAS solid dispersion


Naproxen-PVP solid dispersion


Theophylline, mannitol, diprophylline and tristearin polymorphs


Theophylline anhydrate and monohydrate


the ability of CARS microscopy to perform chemically specifi c imaging without labeling the compound of interest [7]. After identifying the distribution of API within the polymer matrix, they went a step further and imaged the drug release from the matrix in a static medium using CARS microscopy using video rate imaging.


The fi rst work performed using CARS microscopy to image drug release with dynamic dissolution medium was conducted by Windbergs et al. [8] and Jurna et al. [9]. They studied theophylline containing tablets and lipid extrudates and found that during dissolution, theophylline monohydrate crystals grew on the surface of the theophylline tablets but not on the surface of the lipid extrudates. Fussell et al. [10] extended the dissolution concept by incorporating CARS microscopy into an intrinsic dissolution setup. They also studied the dissolution of theophylline (Fig. 2) and found that the surface monohydrate crystal growth visualized by Windbergs et al. [8] signifi cantly reduced the dissolution rate of theophylline anhydrate. They also found that the addition of methyl cellulose to the dissolution medium delayed the monohydrate crystal growth and changed the crystal morphology resulting in an improved dissolution rate for theophylline anhydrate.


The more recent development of SRS allowed Wang et al. [11] to study the distribution of griseofulvin within hydroxypropylmethylcellulose (HPMC) fi lms. SRS provides the same chemically-specifi c rapid imaging available with CARS microscopy and it is has reduced background noise.


Slipchenko et al. [12] published the fi rst work using SRS analyzing commercially available amlodipine besylate tablets. They were able


58 | | September/October 2013 - 15TH ANNIVERSARY ISSUE


Multiphoton techniques were explored for selective detection of model APIs in mixtures with common excipients


Distribution of griseofulvin particles was mapped


SHG enables sensitive quantifi cation of the extent of crystalline material in drug-polymer solid dispersions


Hyperspectral CARS capable of identifying multiple solid-state forms of the same compound


In situ CARS microscopy of theophylline dissolution correlated polymorphic conversions with dissolution rate changes


Reference [3]


[35] [7] [5] [6] [36] [8, 9] [4]


[12] [14]


SHG is able to quantify trace crystallinity within bulk scattering powders [15] [18]


[15] [16]


SHG used to analyse naproxen crystal growth at diff erent temperatures [16] [13]


[10]


Figure 2. Single-frequency CARS images (2952 cm-1


) of


theophylline monohydrate crystals growing on the surface of a theophylline anhydrate compact undergoing dissolution using water as the dissolution medium. Still images from a dissolution video show progressive crystal growth. Reprinted from [10] with permission from Elsevier.


to map the drug and excipient distribution and use these results for comparison between amlodipine besylate formulations from diff erent manufacturers. The authors conclude that SRS microscopy shows good prospective in evaluation of particle size, structural integrity and homogeneity of APIs and excipients in pharmaceutical dosage forms.


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