Simo-Pekka Simonaho

In-line ultrasound measurement system for detecting tablet integrity.

An ultrasound measurement system for tablet defect detection is introduced. The measurement system was implemented in an eccentric single station tabletting apparatus, where ultrasound transducers were placed inside the upper and lower punches. These instrumented punches were then used to measure the speed of sound and ultrasound attenuation values in both intact and defective tablets made from dibasic calcium phosphate, microcrystalline cellulose and lactose monohydrate. Ultrasound attenuation was found to be a very sensitive method to discriminate defective tablets from intact ones. In addition, it was found that the determined ultrasound attenuation was different between all three materials used in this study, which indicates that different materials could be distinguished from one another by this detection method.

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.

Ultrasound transmission measurements for tensile strength evaluation of tablets

Ultrasound transmission measurements were performed to evaluate the tensile strength of tablets. Tablets consisting of one ingredient were compressed from dibasic calcium phosphate dehydrate, two grades of microcrystalline cellulose and two grades of lactose monohydrate powders. From each powder, tablets with five different tensile strengths were directly compressed. Ultrasound transmission measurements were conducted on every tablet at frequencies of 2.25 MHz, 5 MHz and 10 MHz and the speed of sound was calculated from the acquired waveforms. The tensile strength of the tablets was determined using a diametrical mechanical testing machine and compared to the calculated speed of sound values. It was found that the speed of sound increased with the tensile strength for the tested excipients. There was a good correlation between the speed of sound and tensile strength. Moreover, based on the statistical tests, the groups with different tensile strengths can be differentiated from each other by measuring the speed of sound. Thus, the ultrasound transmission measurement technique is a potentially useful method for non-destructive and fast evaluation of the tensile strength of tablets.

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.

Real-time tablet formation monitoring with ultrasound measurements in eccentric single station tablet press.

A real-time ultrasound measurement system for tablet compression monitoring is introduced. The measurement system was tested in actual manufacturing environment and found to be capable of measuring the ultrasound response of the tabletting process from bulk to tablet. The tablet sets were compressed and the ultrasound measurements were conducted as implemented in eccentric single station tabletting apparatus in through transmission geometry. The speed of sound and ultrasound spectrum was measured during dynamic compression for microcrystalline cellulose/paracetamol tablets. The ultrasound system introduced in this study was found to be suitable for tabletting process monitoring as the mechanical properties of compressed tablets can be estimated during compression using the ultrasound system. In addition, it was found that the ultrasound was sensitive to the mixing time of magnesium stearate and the concentration of paracetamol. Thus, ultrasound measurements made during the compression can be used to monitor the tablet formation process.

Achieving a robust drug release from extended release tablets using an integrated continuous mixing and direct compression line.

In the present work the viability of integrated continuous mixing and compression processes for manufacturing of extended release (ER) matrix tablets was investigated in terms of dissolution behavior. The purpose was also to evaluate the combined effect of processing variables and compositional variables on the release robustness. The continuous process was provoked by a challenging formulation design, including variable powder characteristics and compositions of high and low amount of poorly soluble and poorly flowing drug substance (ibuprofen). Additionally a relatively low amount of two different ER matrix former grades (standard granulation grade CR and direct compression grade DC2 of hydroxypropyl methylcellulose, HPMC) was used to challenge the system. Robust ibuprofen release was obtained faster when HPMC CR was used. However, robust release was also achieved when using HPMC DC2 at high ibuprofen content, even though it took slightly longer time to reach the steady state of the process. Due to its poor flow properties, HPMC CR would be very challenging to use in traditional direct compression. The results showed that by using continuous processing it is possible to manufacture and achieve robust performance of compositions that would not be possible with traditional batch processing due to for instance poorly flowability.

Audio acoustic modeling using full‐wave methods

The numerical simulation of wave propagation poses a significant challenge in scientific computation. Historically, several approaches are explored in order to get a stable method that can be efficiently used for approximating wave propagation without excessive numerical dissipation or dispersion. Unfortunately, the traditional approaches, such as the finite element and the finite difference, require many discretization points per wavelength to obtain reliable solutions. In this study, two alternative full‐wave methods for reducing the computational complexity are consider. The methods are the time‐domain discontinuous Galerkin method and the ultraweak variational formulation in the frequency domain. Using these techniques, the directivity and the frequency response of a loudspeaker are studied. Moreover, the simulated results are compared to experimental measurements.

Measurement of diffracted pressure fields using an automated measurement system.

The theory of sound diffraction has been studied widely. Different modeling methods for sound diffraction have been proposed. Some of these modeling techniques are also used in the room acoustic modeling. In this study, diffracted pressure fields from a thin panel were measured. In the measurements, a loud‐speaker was used as a sound source and diffraction from a thin panel was measured. The measurements were performed in small semianechoic chamber using a three‐dimensional 3‐D automated position system. This system consists of a 3‐D position system, a data acquisition hardware, and a control unit. With this system, it is possible to measure diffracted pressure fields with high‐spatial accuracy. In addition, numerical simulations are used in the modeling of sound diffraction from a thin edge. Finally, the simulated pressure fields are compared to the measured fields.

High‐order parallel discontinuous Galerkin method for time‐domain acoustic simulations.

The modeling of acoustic waves in the time‐domain poses a significant challenge in scientific computing. A promising candidate for solving the three dimensional wave equation is the discontinuous Galerkin (DG) method. Advantages of the DG method are the easy parallelization and a special matrix structure which can reduce the overall time and the computer memory needed for solving the problem. In this study, a high order parallel DG method is investigated. The DG solver is implemented using the C++ programming language. Communication between processors of the parallel computer is performed using the message passing interface. In the solver, the polynomial degree of the basis functions is chosen individually for each element of the computation mesh (up to ninth order polynomials can be used). The unbounded problem is truncated using the perfectly matched layers. The method is evaluated with numerical simulations that are performed on a personal computer cluster.