Air-Coupled Acoustics: Sound PAT for Tablet Characterization
A non-destructive, online technique aims to meet the increasing demands of tablet quality.
By Ilgaz Akseli and Cetin Cetinkaya, Clarkson University
Physical (mechanical) properties and mechanical defects (e.g., cracks, capping and delamination) of drug tablets may affect their therapeutic functions1,2. Here, a non-contact/non-destructive acoustic technique for determining the mechanical properties such as Young’s moduli, Poisson’s ratios and mass densities of the core and the coat materials and coating thickness of tablets with mono-layer coating layer is described. These properties are critical to the design of tablets and the performance evaluation of the relevant manufacturing processes. The current method is based on air-coupled excitation of a tablet and the interferometric detection of its vibrational motion.
Many modern commercial tablets consist of two basic structural parts: the core and coating layer(s). Since the core of a typical tablet contains a mixture of one or more active pharmaceutical ingredients (APIs) with a number of inactive excipients, containing diluents, binders and lubricants, we consider a tablet as a mechanical drug delivery device consisting of bonded functional and structural parts (e.g., core and coating layers). For instance, it has been known that the Young’s modulus of a material compacted into solid dosage can often be related to its mechanical hardness3, and hard tablets may impact disintegration time4,5 and thus the release rate of the medicament in the digestive tract, potentially affecting therapeutic response. For many drug products administered in solid dosage form, tablet coating thickness is an important critical-to-quality (CTQ) attribute of the final product6. Tablets are coated to control release of active ingredients in the body, to avoid irritation of the esophagus and stomach, to protect the drug from oxidation and hydrolysis (from humidity in the air), to provide a barrier to unpleasant taste or odor and to protect the stomach from high concentrations of active ingredients. Also, coatings can provide an aesthetic or identification function, provide mechanical strength to the tablet core and in some types, such as enteric coats, improve drug effectiveness and stability and regulate and/or extend dosing interval. Mechanical properties of the core and the coat materials and coating layers play a key role in drug bioavailability, stability and shelf life of a tablet. Cracked or damaged coating could subject the patient to hyper-therapeutic levels of drug. With the advent of new tablet types such as osmotic pumps, push-and-pull and multi-layered tablets, the mechanical structures of some solid dosage forms have become quite complex, requiring complicated tablet architecture as well as patient-friendly administration. Therefore, these types of tablets require more exacting testing and monitoring techniques and faster information return rates than possible with existing techniques.
Quality Control and Quality Assurance (QC and QA) functions play a major role in every industry; however, their effects in the pharmaceutical industry are very prominent since drug formulations are used to treat patients. There are stringent regulatory requirements that must be met in order to market the drug. Also, the regulatory approval process has become significantly more complex and costly. The regulatory agencies are more sophisticated, capable, cautious and conservative in evaluating drugs than in the past. Consequently, their standards for approvals are significantly higher. This, in turn, is forcing pharmaceutical companies to test their new treatments in larger, more comprehensive and more costly clinical trials6. As a result, the demand for measuring and evaluating the mechanical properties of tablets and for monitoring tablet quality has been increasing. For example, for comprehensive quality assurance monitoring in the pharmaceutical industry, the U.S. Food and Drug Administration (FDA) has initiated a guidance program, Process Analytical Technology (PAT)7, which is defined as a system for designing, analyzing and controlling manufacturing through timely measurements (i.e., during processing) of critical quality and performance attributes of raw and in-process materials and processes with the goal of ensuring final pharmaceutical product quality. Such procedures would be consistent with the basic tenet of “Quality by Design” and could reduce risks of quality and regulatory concerns while improving efficiency7. PAT encourages8 the use of acoustic techniques2,9,10 as well as other critical techniques including NIR11, acoustic emission AE12, light-induced fluorescence LIF13, Terahertz-pulsed spectroscopy14, laser induced breakdown spectroscopy (LIBS)15, x-ray fluorescence method16 and Fourier transform infrared (FTIR) spectroscopy17 for characterization and monitoring of tablets by using on-, in- and/or at-line measurements.
Compared to the characterization and monitoring techniques mentioned above, the non-contact/non-destructive acoustic technique detailed here could have potential advantages in testing and evaluating the mechanical integrity of the core and the coat materials and the coating layer thickness of tablets such as suitability for rapid (microsecond-scale time scale) on-line characterization and coating thickness determination applications that eliminate the time lag associated with off-line techniques18,19 and can be cost-effective compared to other measurement techniques13-17.
To demonstrate the utility and effectiveness of the presented non-contact characterization technique, a set of 15 tablets (commercially available) with the average mass of 477 mg and with the characteristic dimensions of 6.32 mm thickness, 11.35 mm diameter and a coating thickness of 135 μm are employed in the experiments (Fig. 1).
Figure 1. The dimensions of the tablet with its top (a), side views (b) and the microscope image of the cross-section of the tablet (c) at 100×. The tablet thickness is determined as 135 µm.