TeraSolve – a porosity measurement tool for the pharmaceutical industry
This module is an addition to the TeraPulse LX product-range. It has been optimized for non- destructive determination of the disintegration and dissolution performance of finished pharmaceutical tablets and other solid dosage forms.
Based upon TeraView’s proprietary semiconductor based THz pulsed technology and over 70 Patented technologies and processes, the system yields real time monitoring of the dissolution properties of tablets during manufacture.
It is based on many years of experience in tablet imaging accumulated through work with TeraView customers and collaborators. In particular ground- breaking work with the University of Cambridge and Huxley Bertram Engineering.
The system may be integrated into full production environments for in-line for ribbon blend measurements, on-line in a tablet press or continuous manufacturing environments. A further configuration is a fully integrated solution with the Huxley Bertram HB50 tablet simulator for formulators and pilot production.
Pharmaceutical – Drivers
We have developed a rapid, non-destructive test method for predicting tablet performance, based on direct measurements of tablet porosity using terahertz pulses. The ultimate goal is to act as a real-time, in-line test as the industry moves towards Continuous Manufacturing.
Traditionally, quality control of pharmaceutical tablets is achieved by batch-testing the end-product. Recently, regulators have recognised that this approach is stifling innovation and results in unnecessarily high manufacturing costs and have initiated the Quality-by-Design (QbD) and Process Analytical Technology (PAT) initiatives, to reduce the cost of manufacturing, by reducing waste and speeding up the development process, whilst enhancing the product quality. However, this can only be achieved by the use of innovative process analysers which are capable of assessing the quality of a large number of samples in a short period of time.
Pharmaceutical - Requirements
The current methods of quality testing of pharmaceutical tablets are destructive and time-consuming dissolution and disintegration tests, which cannot be applied for the control of a large quantity of tablets. The quality control of tablets is thus routinely conducted by the destructive hardness test combined with tablet weight measurements. These measurements do not adequately predict drug performance. In addition, the destructive nature of the hardness test severely limits the number of assessed samples and thus results in little statistical significance.
The bulk density must be uniform within the entire tablet matrix, which is not normally the case. The method also requires careful calibration using complex chemometric models which need to be developed, transferred and maintained by experts.
Tablet porosity directly affects mechanical and permeability properties, and hence the tablet’s disintegration and dissolution behaviour which ultimately determines the bioavailability of an orally administered drug. Porosity is therefore an important quality attribute for pharmaceutical tablets and the ability to measure this property accurately and quickly offers great benefits during drug development and manufacture. The TeraSolve tablet measurement system and software helps provide insight and understanding during research and development of solid dosage forms. The system can also be used during tablet production to provide greater assurance of product quality and potentially facilitate real-time release testing.
Pharmaceutical - Principle of Operation
When a terahertz pulse is transmitted through a solid material, it is slowed down because the refractive index of the material is greater than that of air. By measuring the time delay between a sample pulse and a reference pulse very accurately, and knowing the thickness of the material, we can calculate the effective refractive index of the material neff
For compacted tablets, as the volume fraction of air (i.e. porosity) increases and there is more air space between particles, the effective refractive index neff decreases. At the same, the dissolution/disintegration rate of that tablet will increase.
Measuring neff can therefore be used as a means of predicting dissolution rates, for a particular shape and formulation of tablet. By correlating the dissolution rate vs neff using a teaching batch of tablets, the dissolution rate of subsequent tablets can be predicted simply by measuring the neff using a terahertz measurement system.
The technique can also be used to investigate the effect of tablet manufacturing parameters on porosity e.g. particle size, ribbon thickness, compaction force, tablet size etc.
TeraSolve – the test and measurement tool
TeraSolve is a portable, modular system that gives the user both flexibility and expandability for test & measurement using free space terahertz pulses in the range 60 GHz – 6 THz. User-exchangeable plug and play modules allow for easy reconfiguration or extension of measurements. All systems include TeraView’s patented laser-gated photo-conductive emitters & detectors, as well as patented optical delay line/single laser system.
The system is driven by an ultrafast (90 fs) laser supplied by Calmar Laser to provide broad frequency coverage and unprecedented stability.
The system includes TeraView’s TeraPulse Lx core unit, which has an extensive track record of operation in the field in different applications.
The TeraSolve system is comprised of:
The TeraSolve system is a new addition to the TeraPulse Lx product range. It has been optimized for non-destructive determination of the disintegration and dissolution performance of finished pharmaceutical tablets and other solid dosage forms.
The product stems from recent ground breaking work with the University of Cambridge and Huxley Bertram Engineering, together with a major pharmaceutical manufacturer. The basic system is manually-fed for low throughput applications but the system may be integrated into full production environments for in-line ribbon blend measurements, or with a tablet press.
This includes the following features:
- A platform to allow tablets to be loaded manually by an operator into the carousel.
- A stop/start indexing carousel that enables regular feeding of tablets into the system, and precise presentation to the sensors.
- Measurement of the tablet thickness by means of two laser-based distance sensors.
- Presentation of the tablet to the Lx Sensor Heads.
- Guide and slot to allow ejection of measured tablets. The slot allows collection of the tablets into a container below.
- Simple start/stop controls and an Emergency Stop.
|Dimensions of base unit:||433 mm (w) x 450 mm (d) x 222 mm (h)|
|Dimensions of Tablet Handler:||530 mm (w) x 410 mm (d) x 700 mm (h)|
|Calibration:||Fully automated calibration procedure|
|Sampled Area:||Spot size of Ø1-2 mm|
|Sample shape:||Most tablet shapes and sizes are possible (the carousel is machined to suit)|
|Measurement Rate:||10 tablets/minute|
|Approx weight:||Base unit ~32kg, Tablet Handler ~45 kg|
|Communications:||Ethernet connection to fixed IP address on internal PC|
|Power requirement:||110/220 V, 20 A line power, earthed, via standard 3-pin connection for tablet handler 110/230 VAC, 50Hz single phase, 200 W for base unit|
|Control PC:||Laptop included|
|Operating temperature:||18 °C (64 °F) – 29 °C (84 °F)|
|Operating humidity:||20 – 80%|
Note: The customer needs to provide a weighing scale accurate to ±0.1 mg, for calibration purposes.
Customer Case Study
Ibuprofen was formulated as IR tablets with dose strengths of 10% w/w . Flat-faced tablets with diameter of 9 mm were prepared at three different pressures (50, 100 and 200 MPa), and two rotational speeds (10 and 30 rpm), giving six batches, using the rotary press, Korsch XM 12 (Korsch, Germany). Thousand tablets were compacted per batch. About 250 tablets per batch were measured and analysed.
Both terahertz transmission and thickness measurements of all tablets were simultaneously conducted using the fully automated TeraSolve system.
To predict the disintegration time of the tablets, a standard disintegration test (DT50, SOTAX AG, Switzerland) was performed on 12 tablets per batch and used as the training set.
The measured terahertz porosity (ƒTHz) for all six batches this is shown in the figure below. From this possible to use mean and standard deviation analysis methods on the porosity data to examine the significance of the impact of pressure and speed on the batch porosity. The values of porosity were found to decrease with increasing compaction pressure and increase with increasing rotational speed. It was also observed that high compaction pressures with low rotational speeds yield tablets with less (absolute) variations in porosity.
Prediction of Tablet Disintegration
A correlation based on polynomial regression (where R2 = 0.98, and RMSE = 0.44 mins) was derived between the disintegration time (DT) and the terahertz porosity as:
DT=0.024 ƒ2THz – 1.204 ƒTHz + 15.08 (1)
Equation (1) was then used to predict the disintegration time of all the batches as shown in the Figure below. It was noted that the lowest pressure batch at 50 MPa failed the normality test. This batch is normally not used in production and will have a skewed distribution as there is a natural limit of zero time for disintegration. Again, the p-values from the ANOVA showed the significant impact of compaction pressure and speed on the tablet disintegration. However, unlike porosity, the impact of the interaction term between pressure and speed on disintegration seems to be less significant. Due to the large number of tablets measured outliers can be readily identified and sorted for additional investigation.
This study has demonstrated the use of the newly developed at-line terahertz sensor, TeraSolve for a fast and non-destructive porosity and disintegration measurement of immediate release tablets. The ability to quantify subtle differences in tablets porosity and disintegration makes TeraSolve a promising tool to resolve the concerns raised above.
Reproduced with permission from “Insight into the impact of compaction process variations on tablet disintegration by non-destructive at-line terahertz porosity sensing,” Prince Bawuah et al., University of Cambridge.