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Rapid approaches for exploring solid form landscape

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Fig.1: Stepwise high-throughput approach and factors to be considered during each step (1) Fig.1: Stepwise high-throughput approach and factors to be considered during each step (1)

The major challenge during preformulation is to gain the greatest possible knowledge about candidate drug compounds with minimal use of resources. Therefore, rapid approaches are proposed for identifying critical conditions for existence of various solid forms so that sudden appearance of new forms and unpredictable stability issues can be avoided during later stages of product development.

A High-Throughput Platform for Understanding Factors Affecting Physical and Chemical Stability

Water-solid interactions and especially water sorbing potential of excipients can have a dramatic effect on solid form stability of drug compounds (2-5). Therefore, a high-throughput approach has been recently developed to evaluate influence of excipients on hydration and dehydration behavior under various conditions (1). Fig. 1 delineates the step-wise high-throughput approach and factors to be considered during each step. The same approach can be kept as simple as using only binary mixtures (1:1) with 1 processing factor at 2 different levels (as used in the case study described below) or more comprehensive Design of Experiments (DOE) plan can be performed with binary/ternary mixtures and several processing conditions at various levels and/or under various storage conditions. The level of complexity depends on the stage of NCE in development.

Both studies were performed using only 130 mg of the drug.

 The detailed experimental design can be built with various predictive DOE models and critical quality attributes can be identified. Multivariate data analysis with principle component analysis can be applied for getting a quick overview of the results obtained (6). Furthermore, such a high-throughput platform can also be combined with UV-imaging technique (7, 8) to get the quick overview of dissolution behavior in the presence of different excipients. The comprehensive outcome from this approach will help to eliminate worst case scenarios and/or to develop strategies to mitigate the same during early drug development. At the same time, it can also give information to solid state scientists if there is appearance of new polymorph under any of explored conditions. This can help in avoiding sudden appearance of new forms during later stages of development or even after the product launch.


Four model drugs (sodium naproxen, theophylline, amlodipine besylate, nitrofurantoin) and ten excipients were selected. Binary physical mixtures of drug and excipient (15 mg total) were prepared in 96-well plate followed by addition of two different water levels. The wet samples were subjected for 3 consecutive XRPD measurements (W1,W2,W3) (Fig. 2) followed by drying at 60°C and subsequent XRPD (D1) and HPLC analysis (1).


Nature of the drug and excipients as well as amount of water addition were critical factors influencing phase transformation behaviour. Fig. 3 depicts PCA scores and loadings plot for theophylline samples. Some of the hygroscopic excipients (low-substituted hydroxy propyl cellulose, microcrystalline cellulose) could partially hinder the transformation of anhydrate to monohydrate form; while, extremely hygroscopic excipients, such as Syloid 244FP was able to completely prevent formation of monohydrate by absorbing water itself and reducing microenvironmental water activity. Unknown solid forms were detected for nitrofurantoin and theophylline samples in alkaline environment. Salt disproportionation was detected for sodium naproxen samples in acidic microenvironment (1).

A 3D Emperical Phase Diagram for Identifying Regions of Stability for Various Hydrate Forms


Dynamic vapour sorption analysis (DVS) was performed at temperatures from 25-50°C in steps of 5°C. The humidity was varied with a ramping rate of 5% RH in the range of 10-95% in two sorption/desorption cycles. The DVS results were correlated with structural changes observed using variable-humidity X-ray powder diffraction (9).


Three-dimensional plotting of the multi-temperature DVS data provides a graphical representation of weight gain as a function of both temperature and humidity. This can be considered loosely as empirically-derived phase diagram. Fig. 4 depicts the data for the first sorption cycles at different temperatures. The diagram refers specifically to transformations in the direction of sorption cycle. It can be seen from the diagram that monohydrate (MH) can only be formed from anhydrate (AH) at temperatures above ca 40°C, and tetrahydrate (TH) can exist only below ca 45°C. The plateaux in the plot identify the stable regions for existence of various solid forms. Accordingly, MH, DH-I (dihydrate-I), DH-II (dihydrate-II) and TH were generated by exposing AH in desiccators for around 1 week at 50°C/50% RH, 50°C/80% RH, 25°C/55% RH and 25°C/95% RH, respectively; and they can be stabilised atleast until 3 months under same conditions (confirmed with XRPD) (9). 

Implications of the Suggested Approaches

The proposed rapid approaches can be used during early drug development (i) to simulate typical conditions during secondary manufacturing in a very small scale and to understand possible phase transformation behaviour and influence of excipients on this. (ii) to obtain a quick overview for the relative stability of various anhydrate-hydrate forms under multi-temperature/humidity conditions. The approaches may help understanding the critical parameters affecting physicochemical stability of the drug compound, which can be used in the later stages of development as a prior knowledge for building the design space for implementation of QbD approach ensuring quality pharmaceutical product. 


1.    Raijada D, Cornett C, Rantanen J. A high throughput platform for understanding the influence of excipients on physical and chemical stability. Int J. Pharm. http://dx.doi.org/10.1016/j.ijpharm.2012.08.025

2.    Airaksinen S, Karjalainen M, Kivikero N, Westermarck S, Shevchenko A, Rantanen J, et al. Excipient selection can significantly affect solid-state phase transformation in formulation during wet granulation. AAPS PharmSciTech. 2005;6(2):E311-E22.

3.    Christensen NPA, Cornett C, Rantanen J. Role of excipients on solid-state properties of piroxicam during processing. J. Pharm. Sci. 2012;101(3):1202-11.

4.    Christensen NPA, Rantanen J, Cornett C, Taylor LS. Disproportionation of the calcium salt of atorvastatin in the presence of acidic excipients. Eur J Pharm Biopharm. 2012;82(2):410-6.

5.    Zografi G. States of Water Associated with Solids. Drug Dev Ind Pharm. 1988;14(14):1905-26.

6.    Jørgensen AC, Miroshnyk I, Karjalainen M, Jouppila K, Siiriä S, Antikainen O, et al. Multivariate data analysis as a fast tool in evaluation of solid state phenomena. J. Pharm. Sci. 2006;95(4):906-16.

7.    Boetker J, Rantanen J, Rades T, Müllertz A, Østergaard J, Jensen H. A New Approach to Dissolution Testing by UV Imaging and Finite Element Simulations. Pharm Res. 2013 http://dx.doi.org/10.1007/s11095-013-0972-0

8.    Boetker JP, Savolainen M, Koradia V, Tian F, Rades T, Müllertz A, et al. Insights into the Early Dissolution Events of Amlodipine Using UV Imaging and Raman Spectroscopy. Mol Pharmaceut. 2011;8(4):1372-80.

9.    Raijada D, Bond A, Larsen F, Cornett C, Qu H, Rantanen J. Exploring the Solid-Form Landscape of Pharmaceutical Hydrates: Transformation Pathways of the Sodium Naproxen Anhydrate-Hydrate System. Pharm Res. 2013;30(1):280-9.

PSSRC Facilities

The group of Prof. Jukka Rantanen in Copenhagen has extensive experience in high-throughput technologies both for small and large molecules and the facility is equipped with high-throughput stage both for XRPD analysis and Raman spectroscopy. XRPD instrument is also equipped with variable humidity-temperature AP stage.   

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