Luis Carey and Danna Ritter | Pharmacentral.com Guest Writers

This study explores the use of Raman mapping to monitor blend homogeneity and low dose content uniformity of active pharmaceutical ingredients in excipient blends. Compared with wet chemistry analytical methods, this technique offers a high spatial resolution (several µm), allows the identification of specific components using marker vibrational bands and is non-destructive.

Introduction

Direct compression is by far the most preferred technique in pharmaceutical R&D and tablet production. It involves simply blending the active pharmaceutical ingredient with appropriately selected excipients which are then compressed into tablets. Thus, it eliminates many of the tedious steps that accompany wet granulation.

However, direct tablet compression can be challenging for low dose, highly lipophilic drug substances when it comes to physical stability, blend homogeneity and ultimately, content uniformity. Particular attention needs to be paid to the types of filler-diluent selected as it constitutes the bulk of the formulation.

It has also been suggested that some excipients that are fibrous in nature are ideally suited to direct compression of low dose formulations because they can help trap and ‘bind’ the active drug substance thereby preventing segregation. For more on formulation of low dose see Rohrs, Amidon and Meury et al (2006) article on formulation of low dose formulations here.

During new formulation development, it is vitally important for formulators to have access to simple but effective methods to study drug-excipient interactions beforehand as opposed to laborious wet chemistry techniques that are typically used. Furthermore, assessing the content uniformity this way requires grinding 20 or more tablets which can easily hide variations that would otherwise be visible in physical blends.

By investigating different excipients with a low dose of an API during the blending process it is possible to increase the probability of consistently producing a solid dosage form with acceptable and consistent homogeneity.

In this study, we selected three commonly used functional excipients, namely, pregelatinised starch (LYCATAB® – Roquette), Calcium Phosphate Dihydrate (EMCOMPRESS® – JRS Pharma) and Spray dried lactose (FASTFLOW® – Kerry) commonly used in the formulation of a wide range of solid dosage forms. The aim was to understand the mechanisms behind the physical interactions of the excipients with a micronized, lipophilic drug candidate using Raman FTIR spectroscopy.

Methods

Blends of indomethacin {m.w 357.79, calculated log P 4.18, D (v,4,3) 9.497)] and pregelatinized starch, spray dried lactose and calcium phosphate dihydrate were dry blended in an Apex double cone blender for 10 minutes. Samples (200 mg) were removed in triplicate from different positions within the blender using a stratified sampling technique.

Scanning electron microscope (SEM) is a type of electron microscope capable of producing high resolution images of a sample surface. Due to the manner in which the image is created they have a characteristic three-dimensional appearance and are useful for judging surface structure. SEM images were obtained for indomethacin, pregelatinized starch, spray dried lactose and calcium phosphate dihydrate and the blends thereof. The images were used to approximate particle size and investigate the nature of the interaction between the excipient and the active drug substance.

Laser sizing – Light from a laser is shone into a cloud of particles which are suspended in a transparent gas e.g. air. The particles scatter the light, smaller particles scattering the light at larger angles than bigger particles. The scattered light can be measured by a series of photodetectors placed at different angles. This is known as the diffraction pattern for the sample. The diffraction pattern can be used to measure the size of the particles using light scattering theory. Laser sizing was used to obtain the particle size of both the pregelatinised starch and indomethacin. The results were compared to those obtained by SEM to confirm particle size.

FT-Raman Spectroscopy mapping – This spectroscopic technique investigates the vibrational transitions of covalent bonds in molecules. Raman spectroscopy can be applied to a wide range of samples that includes organic and inorganic materials. FT-Raman spectra of indomethacin in the excipient blends were obtained between 0 and 4000 cm^-1 using a Thermo- Nicolet NXR FT-Raman Spectrometer, equipped with a NXR Genie detector (liquid nitrogen cooled) and a computer controlled mapping stage.

Initial data acquisition was by Smart ARK and OMNIC software. The data were subsequently analyzed using the InSight chemometrics software package. A standard configuration was used to obtain a Raman spectrum from different small areas of drug and excipient blends. Vibrational bands at 1698 cm^-1 (indomethacin), 363 cm^-1 (lactose), 478 cm^-1 (pregelatinized starch) and 988 cm^-1 (calcium phosphate) were used for analyses; from which FT-Raman spectroscopic maps of the blends were obtained.

Results & Discussion

Particle size data of the materials obtained by laser sizing are given in μm in the table below. D10 means that 10% of the particles are below the value stated, similarly for D50 and D90, 50% and 90% respectively.

Approximate sizes of the raw materials obtained by SEM are given in μm in the table below. Comments on the surface features which are expected to effect the interaction between the active pharmaceutical ingredient and the excipient are also given.

The particle size obtained from both techniques are in very good agreement. There are some larger particles of Indomethacin than were observed by SEM however a relatively small sample is analysed by SEM whereas the laser sizing is a product of several experiments each using a few grams of sample. The particle size and nature of the surface will affect both the ‘flowability’ and lubricating nature of the drug substance and excipient when they are subjected to shear in a typical the blending process.

In the case of pregelatinized starch, it is clear that the Indomethacin is attaching to the surface of that starch particles and ‘nestling’ in the crevices between the particles. The “plate-like” shape appears to be beneficial to the interaction and the distribution of Indomethacin throughout the sample appears uniform. With respect to the Lactose monohydrate, the indomethacin is held in its pores and surface detects. It appears that there is more Indomethacin observable in the case of the pregelatinised starch. As Calcium phosphate dihydrate is comparatively more crystalline, it is more difficult to observe Indomethacin on the surface and therefore difficult to compare to the other two excipients.

In each of the following Raman maps of the indomethacin excipient blends, the marker chosen is for Indomethacin; therefore red and yellow indicate the presence of Indomethacin, green and blue indicate the lack of Indomethacin. It is postulated that the yellow is indicative of Indomethacin near the surface, whereas red is at the surface. This is because there is still the characteristic intensity associated with Indomethacin present however, in the case of the yellow bands, it is not as significant as the red implying that the laser is not as focused on the Indomethacin at this point.

Only a very small selection of the maps generated in this study are presented.

Based on spatial maps of indomethacin within the different excipients which were analysed chemometrically, the results showed that pregelatinized starch exhibited good homogeneity and had the lowest agglomeration of the active ingredient. Spray dried Lactose blends showed good homogeneity but the level of agglomeration appeared to be. Calcium phosphate blends had the poorest homogeneity and the highest agglomeration. It is hypothesized that the greater level of particle-particle shear generated during blending facilitated the attainment of more homogeneous distribution of the active ingredient with pregelatinised starch.

Conclusions

SEM showed that for the Calcium phosphate dihydrate the surface was crystalline and irregular whereas the lactose monohydrate it was more porous and pregelatinized starch was amorphous containing plate like structures. These properties are expected to affect the flow ability and lubricating nature of the excipients when they are subjected to shear in the blending process.

On the basis of the results of this study, the following conclusions can be drawn:

SEM can be used to visualise the distribution of Indomethacin in different blends. Calcium phosphate dihydrate proved the most difficult to interrogate as it is so crystalline and broad in its size distribution. It was difficult to observe Indomethacin on the surface. For both Spray-dried Lactose and pregelatinized starch the Indomethacin at the surface was clearly visible either held in the pores or the plate-like surface features of each excipient respectively. The porous structure of the lactose and the plate-like irregular shape of the pregelatinised starch both appear to be beneficial to the interaction and the distribution of Indomethacin throughout the sample.

Raman mapping can be used to monitor blend homogeneity and low dose content uniformity of active pharmaceutical ingredients in excipient blends. This technique offers a high spatial resolution (several µm), enables the identification of specific components using marker vibrational bands and is non-destructive. The results of this study showed that better blend homogeneity was achieved with pregelatinized starch compared with lactose or calcium phosphate.

References

• B.R. Rohrs, G.E. Amidon, R.H. Meury, P.J. Secreast, H.M. King, C.J. Skoug, Particle Size Limits to Meet USP Content Uniformity Criteria for Tablets and Capsules, Journal of Pharmaceutical Sciences, 95 (2006) 1049-1059. https://www.sciencedirect.com/science/article/abs/pii/S0022354916320202. 10.1002/jps.20587
• M. Ficzere, L.A. Mészáros, L. Madarász, M. Novák, Z.K. Nagy, D.L. Galata, Indirect monitoring of ultralow dose API content in continuous wet granulation and tableting by machine vision, International Journal of Pharmaceutics, 607 (2021) 121008. https://www.sciencedirect.com/science/article/pii/S0378517321008140/ DOI: 10.1016/j.ijpharm.2021.121008
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