Tuomas Ervasti

Detection of porosity of pharmaceutical compacts by terahertz radiation transmission and light reflection measurement techniques

We report on the non-destructive quantification of the porosity of pharmaceutical compacts (microcrystalline cellulose tablets) by using both optical and terahertz techniques. For the full analysis of the porosity of pharmaceutical tablets, the results obtained in both cases have shown that optical and terahertz techniques are complementary. The intrinsic refractive index of microcrystalline cellulose was estimated using the effective refractive index obtained from the time delay of the THz pulse together with the Bruggeman model for effective media. Once this intrinsic refractive index is known, the unknown porosity of the tablet can be estimated with the aid of the measured effective refractive index as well as the thickness of the pharmaceutical tablet. The method was tested using a set of thirteen tablets having different porosities. It is shown that the error in the estimation of the unknown tablets porosity is less than 1%. In addition, surface roughness was measured by using an optical interferometer and gloss by using a diffractive-optical-element based glossmeter. The measurement was achieved by scanning the tablets with a probe beam and detecting the reflected light. The surface roughness and gloss data show relatively good correlation with the porosities of the tablets.

Non-contact weight measurement of flat-faced pharmaceutical tablets using terahertz transmission pulse delay measurements.

By measuring the time delay of a terahertz pulse traversing a tablet, and hence its effective refractive index, it is possible to non-invasively and non-destructively detect the weight of tablets made of microcrystalline cellulose (MCC). Two sets of MCC tablets were used in the study: Set A (training set) consisted of 13 tablets with nominally constant height but varying porosities, whereas Set B (test set) comprised of 21 tablets with nominally constant porosity but different heights. A linear correlation between the estimated absolute weight based on the terahertz measurement and the measured weight of both sets of MCC tablets was found. In addition, it was possible to estimate the height of the tablets by utilizing the estimated absolute weight and calculating the relative change of height of each tablet with respect to an ideal tablet. A good agreement between the experimental and the calculated results was found highlighting the potential of this technique for in-line sensing of the weight, porosity and the relative change in height of the tablets compared to a reference/ideal tablet. In this context, we propose a quantitative quality control method to assess the deviations in porosity of tablets immediately after compaction.

A Study on the Resolution of a Terahertz Spectrometer for the Assessment of the Porosity of Pharmaceutical Tablets

In this study, the resolution of a time-domain terahertz spectrometer for tablet porosity measurements was estimated using two sets of pharmaceutical tablets. One set consisted of tablets with constant thickness and with porosity as a variable. The other set consisted of tablets with variable thickness and only a relatively small change in porosity. The set with constant thickness was used for the calibration of the terahertz (THz) spectrometer for the porosity measurements, and the resolution of the terahertz spectrometer was estimated using the set with different thicknesses and slightly different porosities. It was shown that a time-domain THz spectrometer is a sensitive device that allows monitoring of minute changes in the porosity of pharmaceutical tablets by detecting the time delay of the THz pulse, which is attributable to different refractive indices within the tablet.

Continuous manufacturing of extended release tablets via powder mixing and direct compression

The aim of the current work was to explore continuous dry powder mixing and direct compression for manufacturing of extended release (ER) matrix tablets. The study was span out with a challenging formulation design comprising ibuprofen compositions with varying particle size and a relatively low amount of the matrix former hydroxypropyl methylcellulose (HPMC). Standard grade HPMC (CR) was compared to a recently developed direct compressible grade (DC2). The work demonstrate that ER tablets with desired quality attributes could be manufactured via integrated continuous mixing and direct compression. The most robust tablet quality (weight, assay, tensile strength) was obtained using high mixer speed and large particle size ibuprofen and HPMC DC2 due to good powder flow. At low mixer speed it was more difficult to achieve high quality low dose tablets. Notably, with HPMC DC2 the processing conditions had a significant effect on drug release. Longer processing time and/or faster mixer speed was needed to achieve robust release with compositions containing DC2 compared with those containing CR. This work confirms the importance of balancing process parameters and material properties to find consistent product quality. Also, adaptive control is proven a pivotal means for control of continuous manufacturing systems.

Kramers–Kronig analysis on the real refractive index of porous media in the terahertz spectral range

We present a terahertz time-domain experimental technique for the detection of scattering from porous media. The method for detection of the scattering enables one to make a decision when Fresnel or Kramers-Kronig (K-K) analysis can be applied for a porous medium. In this study the real refractive index of a tablet is calculated using the conventional K-K dispersion relation and also using a singly subtractive K-K relation, which are applied to the extinction coefficient obtained from the Beer-Lambert law. The advantage of the K-K analysis is that one gets estimates both for absolute refractive index and also dispersion of the porous tablet, whereas Fresnel analysis provides only the absolute value of the index.

Terahertz study on porosity and mass fraction of active pharmaceutical ingredient of pharmaceutical tablets

In this study, terahertz time-domain spectroscopic (THz-TDS) technique has been used to ascertain the change in the optical properties, as a function of changing porosity and mass fraction of active pharmaceutical ingredient (API), of training sets of pharmaceutical tablets. Four training sets of pharmaceutical tablets were compressed with microcrystalline cellulose (MCC) excipient and indomethacin API by varying either the porosity, height, and API mass fraction or all three tablet parameters. It was observed, as far as we know, for the first time, that the THz time-domain and frequency-domain effective refractive index, as well as, the frequency-domain effective absorption coefficient both show linear correlations with the porosity and API mass fraction for training sets of real pharmaceutical tablets. We suggest that, the observed linear correlations can be useful in basic research and quality inspection of pharmaceutical tablets. Additionally, we propose a novel optical strain parameter, based on THz measurement, which yields information on the conventional strain parameter of a tablet as well as on the change of fill fraction of solid material during compression of porous pharmaceutical tablets. We suggest that the THz measurement and proposed method of data analysis, in addition to providing an efficient tool for basic research of porous media, can serve as one of the novel quality by design (QbD) implementation techniques to predict critical quality attributes (CQA) such as porosity, API mass fraction and strain of flat-faced pharmaceutical tablets before production.

Theophylline-nicotinamide cocrystal formation in physical mixture during storage.

Pharmaceutically relevant properties, such as solubility and dissolution rate, of active pharmaceutical ingredients can be enhanced by cocrystal formation. Theophylline and nicotinamide are known to form cocrystals, for example if subjected to solid-state grinding. However, under appropriate conditions, cocrystals can also form in physical mixtures without any mechanical activation. The purpose of this work was to study whether theophylline and nicotinamide could form cocrystals spontaneously, without mechanical activation. Crystalline theophylline and nicotinamide powders were gently mixed manually in a 1:1 molar ratio and stored at different relative humidity and temperature conditions. The solid state of the samples was analyzed by differential scanning calorimetry, Raman spectroscopy and X-ray powder diffractometry. Three different variations of theophylline were used as starting materials, e.g., two size fractions of theophylline anhydrate (large 710 μm-1 mm and small 180-355 μm), and monohydrate (recrystallized from water). As a reference, anhydrous theophylline-nicotinamide cocrystals were prepared by solid-state grinding. The results of this study indicate that theophylline-nicotinamide cocrystals can form without any mechanical activation from physical mixtures of theophylline and nicotinamide during storage. For anhydrous samples, storage humidity was found to be a critical parameter for cocrystal formation. Increasing temperature was also found to have an accelerating effect on the transformation. The effect of particle size of anhydrous theophylline on the transformation rate could not be completely resolved; DSC and Raman indicated slightly faster transformation with a physical mixture prepared from large size fraction of anhydrous theophylline, but the differences were only minor. Cocrystal formation was also observed in the physical mixture prepared from theophylline monohydrate, but the rate was not as high as with samples prepared from anhydrous material.

A structure parameter for porous pharmaceutical tablets obtained with the aid of Wiener bounds for effective permittivity and terahertz time-delay measurement

A structure parameter that can be used to predict the pattern of arrangement of porous inclusions in pharmaceutical tablets is introduced. By utilizing the effective refractive index of a pharmaceutical tablet obtained from terahertz time-domain measurements, we have shown that there exists a promising correlation between the calculated structural parameter and the porosity of training sets of pharmaceutical tablets, having well-defined characterization. Knowing of the structural arrangement, i.e. combined constituent skeletal-pore elements in series, parallel or mixed within porous media, could serve as a basis for understanding the ingress and permeation of liquids in such media. In the realm of pharmaceutical applications, such knowledge of the structural arrangement of air voids within a medicinal tablet could enable correlation with mechanical strength and dissolution behaviour in aqueous systems.

Continuous manufacturing of tablets with PROMIS-line - Introduction and case studies from continuous feeding, blending and tableting.

Drug manufacturing technology is in the midst of modernization and continuous manufacturing of drug products is especially the focus of great interest. The adoption of new manufacturing approaches requires extensive cooperation between industry, regulatory bodies, academics and equipment manufacturers. In this paper we introduce PROMIS-line which is a continuous tableting line built at the University of Eastern Finland, School of Pharmacy, PROMIS-centre. PROMIS-line is modular and tablets can be produced via dry granulation or direct compression. In three case studies, continuous feeding, blending and tablet performance is studied to illustrate some basic features of PROMIS-line. In conclusion, the PROMIS-line is an excellent tool for studying the fundamentals of continuous manufacturing of tablets.

Noninvasive porosity measurement of biconvex tablets using terahertz pulses

Biconvex pharmaceutical microcrystalline cellulose (MCC) compacts were investigated by the detection of terahertz (THz) pulse delay in the transmission measurement mode. The dimensions of the tablets were kept as constants but the porosity was a priori known variable. It is shown that the porosity of the biconvex compact has a linear correlation with the THz pulse delay. By constructing a calibration line between these two parameters (i.e. porosity and THz pulse delay), it is possible to non-invasively detect porosity of biconvex tablets. We suggest that this preliminary study could be the starting point of in-depth future studies on the screening of porosity and related properties of real biconvex pharmaceutical tablets using terahertz sensing techniques.