SPOT LIGHT

How is X-ray CT being used to ensure quality in tabletting?

Rahul V Haware, Robert Sedlock, Grant Sedlock at Natoli Scientific; Ming Ji at the University of New Mexico College of Population Health; Nitin kumar Swarnkar and Sandip Tiwari at the BASF Corporation; and Angela Criswell at Rigaku Corporation Americas

The tablet is the most popular vehicle for well-controlled, targeted and predictable drug release.1 It offers a consistent and large volume production at relatively low cost with minimum waste. Tablets are composed of active pharmaceutical ingredients (API) and inactive ingredients or excipients. Thus, tabletting properties can be an API driven (API >50%), an excipient driven (excipient >90%) or both API-excipient driven (API >25% and excipient >75%), in addition to applied manufacturing parameters.

These parameters dictate the internal 3-dimensional (3D) tablet skeleton. The changes in microscopic and macroscopic morphology of tablet ingredients and their distribution after compression process across the 3D tablet skeleton dictates the intrinsic and extrinsic tablet attributes and performance. The intrinsic attributes include API and excipients content distribution, pore concentrations, granule morphology, and presence of impurities and solvents. The extrinsic attributes include mechanical strength, coating layer thickness and stability. Extrinsic tablet properties are direct implications of intrinsic properties and resulting tabletting performance.

Traditional testing methods

Various official pharmacopoeial tests are employed to ensure consistent qualities of tablets. However, a traditional surrogative off-line tablet testing could not guarantee consistent tablet qualities as well as detailed insights on a tablet’s internal 3D skeleton required to decode performance failure modes. Poor tablet characterisation could result in poor tablet functionality, which could result in the failing of drug approval or assessment tests, and possible tablet recalls of approved product from the market.2 Therefore, assessing intrinsic and extrinsic characteristics and ensuring their uniformity within the production series is particularly important for the drug development, quality control of optimised manufacturing process, and approval from regulatory agencies like the US Food and Drug Administration (FDA) and European Medicines Agency.

Figure 1: Impact of internal tablet structure of (A) tablets of physical blends of Kollitab DC 87L and (B) Co-processed Kollitab DC87L on (C) ibuprofen release profiles

Figure 2: Tablet capping (A) Side and (B) Front view and X-ray micro-CT scans of (C) OTC Lansoprazole capsule, (D) Lansoprazole granules and (E) Lansoprazole granule defects

The FDA ICHQ8 pharmaceutical development and ICHQ9 quality risk management guidelines have provided various advanced spectroscopic techniques to assess, monitor and manufacture in-built quality tablets.3,4 These spectral techniques include near-infrared, infrared and Raman spectroscopy. However, though these non-destructive techniques provide in-depth chemical profiling of tablets, they do not provide the tablet’s internal 3D physical skeletal information.

Introducing X-Ray CT

A high-resolution X-ray computerised tomography (X-ray CT) provides a non-destructive detailed analysis of density gradients and internal defects such as cracks and voids, as well as internal 3D physical structure. This is vital information during the tablet formulation and development process to decode root cause analysis of both success and failure of manufactured tablets while meeting desired specifications and performance. Furthermore, X-ray micro-CT is a simple and convenient technique for tablet characterisation, as it requires minimal to no additional sample preparation before the experimentation.

Assessing a tablet’s 3D internal physical skeleton

KollitabTM DC87L is a co-processed excipient composed of lactose monohydrate (87%), crosspovidone (9%), Kollitab® IR (3%) and sodium stearyl fumarate (1%). An X-ray micro-CT scan was used to evaluate the tabletting performance of co-processed Kollitab DC87L and the physical blend of its components. The X-ray micro-CT scan generated the 3D internal physical skeleton of this tablet and revealed that tablets made with the physical blend of Kollitab DC87L exhibited several cracks throughout the tablet body (Figure 1). Contrary, the co-processed Kollitab DC87L did not show any cracks. These findings exhibited the better tabletting performance of co-processed Kollitab DC87L as compared to the physical blend of its components. This better tabletting performance of Kollitab DC87L could be attributed to better material deformation of co-processed excipients during the compression cycle.

Detecting tablet defects

A commercial manufacturing of tablets poses four major tabletting defects – lamination, capping, picking and sticking. Capping involves separation of the top or bottom part of the tablet from the main tablet body during the ejection cycle. Tabletting material picking occurs at engraved areas like logos or letters of the punch surface, which causes impression defects on the next tablet. Lamination is another important tabletting defect involving the splitting of tablets into two or more layers parallel to its flat faces. Sticking is a major tabletting problem that involves tabletting materials sticking to the punch surface due to more excessive adhesive forces occurring between the punch face and material than cohesive forces between the tabletting materials. These problems are prominent in the late development stage due to large production batch size. Such problems require a solution without changing the formulation due to regulatory constraints.

Natoli Scientific has generated in-house analytical methodology for both tablet sticking and capping.5 These material-sparing methodologies are based on powder rheological and deformation properties. The proposed methodologies allow the finding out of root causes of tablet sticking and capping, and provide possible pragmatic solutions without changing the formulation.

Coupling of X-ray micro-CT scan with the Natoli in-house capping and sticking methodologies could serve as a powerful tool for root cause analysis of such tabletting problems. Importantly, X-ray micro-CT generated 3D internal physical structure provides clear differentiation between capping, picking and lamination. Figure 2 shows the side and front view of a tablet indicating clear separation of the top layer from the main body of the tablet. This can be identified as tablet capping. Such information is vital to optimise existing formulation by reducing the key parameters responsible for capping such as reducing in-die tablet expansion in the decompression phase or modifying tool designs.

Correlation of tablet structure with dissolution performance

A dissolution performance of ibuprofen Kollitab DC87L and ibuprofen Kollitab DC87L component physical blend tablets were measured with USP II apparatus and 0.1N HCl (pH 1.2) as a dissolution medium. The paddle speed was 75rpm. The temperature of dissolution media was 37 ± 0.5° C. Kollitab DC87L tablets with and without 20% ibuprofen were >3 times stronger than those made with the physical blend. As mentioned previously, X-ray CT scan confirmed a strong and uniform structure of Kollitab DC87L tablets and was compared to its physical mixture tablets (Figure 1). The X-ray CT scan revealed that Kollitab DC87L tablets did not possess any internal cracks, while tablets made with the physical blend of Kollitab DC87L contained a substantial number of internal cracks. As a result, the ibuprofen release from Kollitab DC87L tablets had less variability than that from tablets made with the physical blend of Kollitab DC87L (Figure 1C).

Granule size estimation in capsules

The multi-unit pellet system (MUPS) is a multi-particulate system designed for immediate release, modified drug release and to administer incompatible drugs. These dosage forms contain uncoated as well as coated pellets of functional coatings with variable thickness to achieve desired modified drug release. Therefore, core granule or pellet size distribution and their porosity can affect the modified drug release profile; a pellet with smaller size distribution and high porosity could lead to a rapid disintegration and faster drug release than desired criteria. X-ray micro-CT scans could be a powerful technology to evaluate these features of MUPS. Figures 2C and D show OTC lansoprazole MUPS capsules. These scans reveal varying granule size distribution, viscosity, as well as broken granules (Figure 2E).

Coating uniformity of functional coatings

Tablets are coated for various purposes like protection, taste masking or controlled release. One of the critical parameters of coating layers is coating thickness, uniformity and its distribution. A typical tablet coating thickness varies between 5-100µm. The coating process impacts the coating layer uniformity. Typical industrial coating process uniformity is monitored with tablet weight gain, scanning electron microscopy and with dissolution testing. However, these non-destructive and destructive tests and indirect parameters do not provide real measurements of coating thickness. A non-destructive and high-resolution X-ray micro-CT scan could provide a quantitative measurement of coating thickness, as well as the presence of pores in the coating layer.

Coating uniformity of multi-unit multi-particulate system

Coated pellets along with non-coated pellets or granules are key components of multi-unit multi-particulate systems. These coated pellets or granules have appropriate coating film made with the desired type and amount of polymer. A variation in coating thickness, as well as coating integrity during the shelf life, is important to achieve modified drug release. A non-destructive and high-resolution X-ray micro-CT scan could provide a qualitative and quantitative measurement of coating features. It can provide coating integrity as well as coating layer thickness measurements.

Conclusions

The present study has demonstrated application of a high-resolution X-ray micro-CT as a powerful tool for various solid dosage form characterisations. This non-destructive technology can provide direct correlation of a tablet’s internal structure on the final dosage form performance. It can also serve as a direct methodology for a quantitative evaluation of various functional and non-functional coating features as compared to currently applied indirect methods. Recently, Natoli Scientific has acquired this powerful technology to provide our national and international clients the visibility of invisible features of manufactured solid dosage forms.

References:

1. Lieberman, H.A et al (1980), ‘Pharmaceutical Dosage Forms: Tablets’, Marcel Dekker Inc, Volume 1
2. Bostijn N et al (2018), ‘In-line UV spectroscopy for the quantification of low-dose active ingredients during the manufacturing of pharmaceutical semi-solid and liquid formulations’, Analytica Chimica Acta, 1013, 54-62
3. Visit: database.ich.org/sites/default/files/Q8_R2_ Guideline.pdf
4. Visit: fda.gov/regulatory-information/search-fdaguidance-documents/q9r1-quality-risk-management
5. D Patel KC et al (2021), ‘Powder Rheology: Gateway for Tablet Sticking Insights’, Manufacturing Chemist