Wireless transmission of ultrasonic waveforms for monitoring drug tablet properties and defects.

The geometric and mechanical properties of pharmaceutical materials are crucial to their structural, functional and therapeutic effectiveness. The implementation of automated and convenient quality monitoring procedures is an attempt to balance control of quality against the level of testing; within acceptable levels of probability and costs. The capability of rapid/extensive inspections with minimal time and manufacturing interruption make non-contact quality monitoring systems a desirable approach to optimize this balance. In the current study, a wireless transceiver proof of concept system developed for the real-time quality monitoring of tablets during compaction is presented and demonstrated. The effectiveness of ultrasonic wave transmission through the punch-tablet interface is the boundary condition that dictates the viability of the acoustic in-die compaction monitoring approach. These measurements in the current experimental set-up can be used in determining various mechanical and geometric properties of a compact, such as the tablet thickness, mass density, elasticity and/or integrity of the tablet core, and bonding quality between layers depending on the given parameters, as it is compacted. In the current study, it is demonstrated that the reflection of an ultrasonic pulse generated by a transducer embedded in an upper punch from the lower punch-tablet interface can be acquired by the same transducer in the upper punch and the analog waveform can be transmitted to a computer by means of wireless communications for further signal processing and property extraction. The evolution of apparent Young's moduli of a powder bed during a full-compaction cycle is derived from the ultrasonic time of flight of an acoustic waveform acquired during compaction in-die.

Non-destructive determination of anisotropic mechanical properties of pharmaceutical solid dosage forms.

The mechanical property anisotropy of compacts made from four commercially available pharmaceutical excipient powders (microcrystalline cellulose, lactose monohydrate, ascorbic acid, and aspartame) was evaluated. The speed of pressure (longitudinal) waves in the uni-axially compressed cubic compacts of each excipient in the three principle directions was determined using a contact ultrasonic method. Average Young's moduli of each compact in the axial (x) and radial (y and z) directions were characterized. The contact ultrasonic measurements revealed that average Young's modulus values vary with different testing orientations which indicate Young's modulus anisotropy in the compacts. The extent of Young's modulus anisotropy was quantified by using a dimensionless ratio and was found to be significantly different for each material (microcrystalline cellulose>lactose>aspartame>ascorbic acid). It is also observed that using the presented contact method, compacts at high solid fraction (0.857-0.859) could be differentiated than those at the solid fraction of 0.85 in their groups. The presented contact ultrasonic method is an attractive tool since it has the advantages of being sensitive to solid fraction ratio, non-destructive, requiring small amount of material and rapid. It is noteworthy that, since the approach provides insight into the performance of common pharmaceutical materials and fosters increased process knowledge, it can be applied to broaden the understanding of the effect of the mechanical properties on the performance (e.g., disintegration profiles) of solid oral dosage forms.

NMR search for polymorphic phase transformations in chlorpropamide form-A at high pressures.

The high-pressure effects on chlorpropamide (C10H13ClN2O3S) form-A have been studied by 1H NMR spectroscopy at high pressures up to 800 MPa in the temperature range 90-300 K. A study of the NMR second moment and spin-lattice relaxation time has been completed by a calculation of the steric hindrances for molecular reorientations and simulations of the second moment of the NMR line by the Monte-Carlo method, which enabled a precise description of molecular dynamics in the compound studied. Reorientations of the methyl group, oscillations and reorientations of the chlorophenyl ring and reorientations of the propyl group have been revealed and respective activation parameters extracted. No phase transformation of the compound form-A has been detected.

Process simulation in the pharmaceutical industry: a review of some basic physical models.

This study reviews process modeling efforts which have been developed to elucidate the fundamental physical process underlying the manufacture and delivery of pharmaceutical dosage forms. Within the pharmaceutical industry, process models have been applied to a diverse array of physical processes at length and time scales that vary by orders of magnitude. As such, both large-scale continuum and particle-scale discrete approaches will be discussed in this study. Challenges associated with the practical application of process models within the pharmaceutical industry will be discussed, and opportunities for future research will be identified.

The powder flow and compact mechanical properties of two recently developed matrix-forming polymers.

The powder flow and compact mechanical properties of two recently developed matrix-forming polymers were determined. The polymers are cross-linked high-amylose starch (Contramid) and poly(acrylic acid) (Carbopol EX507), and their properties were compared with those of two established matrix-forming polymers, hydroxypropyl methylcellulose (Methocel K100LV) and hydroxypropyl cellulose (Klucel EXF). The particle morphology, size distribution and true density of the four materials were quite different and they exhibited measurable performance differences with respect to powder flow, compact ductility, compact elasticity and compact tensile strength. Recommendations for formulating solid dosage forms with each of these excipients were made, based on a consideration of their physical properties and their anticipated processing performance.

Micro-scale measurement of the mechanical properties of compressed pharmaceutical powders. 2: The dynamic moduli of microcrystalline cellulose.

The use of two 'micro-scale' dynamic mechanical testing techniques for determining the viscoelastic properties of very small microcrystalline cellulose compacts ( approximately 20 mg) is reported. The first method is a simple tensile 'stretching' test, and the second is a dynamic version of the three-point beam-bending technique. For both approaches the storage (elastic) and loss (viscous) moduli could be readily determined for compacts of a wide range of porosities. The experimentally determined storage moduli were consistently one order of magnitude greater than the corresponding loss moduli indicating a dominating elastic response for the microcrystalline cellulose compacts. The moduli determined using the oscillating three-point beam-bending technique were slightly lower than expected and this was attributed to sample anisotropy and imperfect sample alignment/friction during testing. The moduli obtained using the simple dynamic tension tests were practically identical to complex moduli values reported for much larger specimens, and it appears that this technique is well suited to measuring the dynamic mechanical properties of very small pharmaceutical powder compacts.

Micro-scale measurement of the mechanical properties of compressed pharmaceutical powders. 1: The elasticity and fracture behavior of microcrystalline cellulose.

The feasibility of using very small compacts ( approximately 8.0 x 4.5 x 0.4 mm; approximately 20 mg) to determine the elasticity and fracture behavior of compressed pharmaceutical powders using the three-point beam-bending technique was evaluated. Compacts of microcrystalline cellulose with a range of porosities were tested using a thermomechanical analyzer and values for the Young's modulus and critical stress intensity factor at zero porosity (E(0) and K(IC0)) were determined by extrapolation. The value of E(0) measured at ambient relative humidity on un-notched beams was found to be in close agreement with that reported for much larger samples, and the value of K(IC0) for the small notched compacts was at the lower limit of the accepted range of values for microcrystalline cellulose. The fracture toughness (R) and total energy of fracture (U) for the notched specimens were also determined and used to estimate the apparent surface energies for crack initiation (gamma(i)) and for total fracture (gamma(f)). To further probe the utility of the micro-scale mechanical testing techniques, the effects of humidity on the various mechanical properties of the small microcrystalline compacts were examined and it was found that E(0), K(IC0), R(0), gamma(i0) and gamma(f0) each decreased as the surrounding humidity (and water content of the samples) increased.

What is the true solubility advantage for amorphous pharmaceuticals?

PURPOSE: To evaluate the magnitude of the solubility advantage for amorphous pharmaceutical materials when compared to their crystalline counterparts. METHODS: The thermal properties of several drugs in their amorphous and crystalline states were determined using differential scanning calorimetry. From these properties the solubility advantage for the amorphous form was predicted as a function of temperature using a simple thermodynamic analysis. These predictions were compared to the results of experimental measurements of the aqueous solubilities of the amorphous and crystalline forms of the drugs at several temperatures. RESULTS: By treating each amorphous drug as either an equilibrium supercooled liquid or a pseudo-equilibrium glass, the solubility advantage compared to the most stable crystalline form was predicted to be between 10 and 1,600 fold. The measured solubility advantage was usually considerably less than this, and for one compound studied in detail its temperature dependence was also less than predicted. It was calculated that even for partially amorphous materials the apparent solubility enhancement (theoretical or measured) is likely to influence in-vitro and in-vivo dissolution behavior. CONCLUSIONS: Amorphous pharmaceuticals are markedly more soluble than their crystalline counterparts, however, their experimental solubility advantage is typically less than that predicted from simple thermodynamic considerations. This appears to be the result of difficulties in determining the solubility of amorphous materials under true equilibrium conditions. Simple thermodynamic predictions can provide a useful indication of the theoretical maximum solubility advantage for amorphous pharmaceuticals, which directly reflects the driving force for their initial dissolution.

Interpretation of relaxation time constants for amorphous pharmaceutical systems.

The molecular mobility of amorphous pharmaceutical materials is known to be a key factor in determining their stability, reactivity, and physicochemical properties. Usually such molecular mobility is quantified using relaxation time constants. Typically relaxation processes in amorphous systems are non-exponential and relaxation time constants are usually obtained from experimental data using a curve fitting procedure involving the empirical Kohlrausch-Williams-Watts (KWW) equation. In this article we explore the possible relationship between the KWW curve fitting parameters (tau(KWW), beta(KWW)) and common statistical measures of the average and the distribution (e.g., median, standard deviation) of the relaxation time values. This analysis is performed for several common statistical distributions (e.g., normal, lognormal, and Lorentzian), and the results are compared and analyzed in the context of pharmaceutical product stability predictions. The KWW function is able to describe relaxation processes stemming from several different statistical distribution functions. Under some circumstances the "average" relaxation time constant of the KWW equation (tau(KWW)) is significantly different from common statistical measures of the central value of a distribution (e.g., median). Simply knowing the relaxation time constants from the fit of the KWW equation is not sufficient to completely characterize and quantify the molecular mobility of amorphous pharmaceutical materials. An appreciation of the distribution of relaxation times and the resulting effects upon the KWW constants should be considered to be essential when working with amorphous pharmaceutical materials, especially when attempting to use relaxation time constants for predicting their physical or chemical stability.

Determination of the viscosity of an amorphous drug using thermomechanical analysis (TMA).

PURPOSE: To evaluate thermomechanical analysis (TMA) as a technique for determining the viscosity of amorphous pharmaceutical materials. This property of amorphous drugs and excipients is related to their average rate of molecular mobility and thus to their physical and chemical stability. METHODS: Indomethacin was selected as a model amorphous drug whose viscosity has previously been reported in the literature. A Seiko TMA 120C thermomechanical analyzer was utilized in isothermal penetration mode to determine the viscosity of the amorphous drug over the maximum possible range of temperatures. RESULTS: Using a cylindrical penetration geometry it was possible to accurately determine the viscosity of amorphous indomethacin samples by TMA over the temperature range from 35 to 75 degrees C. The results were consistent with those reported in the literature using a controlled strain rheometer over the range 44-75 degrees C. The limiting lower experimental temperature for the TMA technique was extended to significantly below the calorimetric glass transition temperature (Tg approximately 42 degrees C), thus allowing a direct experimental determination of the viscosity at Tg to be made. CONCLUSIONS: Thermomechanical analysis can be used to accurately determine the viscosity of amorphous pharmaceutical materials at temperatures near and above their calorimetric glass transition temperatures.

The effect of temperature on water vapor sorption by some amorphous pharmaceutical sugars.

To determine the effect of temperature on the water vapor sorption behavior of some amorphous pharmaceutical sugars, aqueous solutions of sucrose, lactose, trehalose, and raffinose were freeze-dried using a conventional laboratory lyophilizer. The amorphous sugars formed were stored for several months at 5, 30, and 50 degrees C and at a range of relative humidities (0-90% RH). After equilibration the extent of water vapor sorption was determined gravimetrically, and the presence of any crystalline material was determined. A significant amount of water was sorbed by each of the amorphous sugars even at moderate humidities. In every system studied, lowering the storage temperature at any given relative humidity caused an increased quantity of water to be sorbed. This indicated the predominance of an exothermic water vapor sorption process. Spontaneous crystallization of all the sugars occurred at elevated RHs, and the onset of crystallization did not necessarily coincide with attainment of the water content of the final crystalline forms(s) or the reduction of the sugars' glass transition temperature to ambient conditions. Notably, the amorphous and crystalline forms of some sugars were able to coexist in a quasi-equilibrium state under certain temperature and humidity conditions.

Water vapor sorption by peptides, proteins and their formulations.

The interactions of pharmaceutical peptides, proteins and their formulations with environmental water vapor are reviewed. Particular attention is paid to the importance of the physical structure and chemical diversity of peptides and proteins, and comparisons are made with the mechanisms of water vapor sorption by synthetic macromolecular systems. The influences of formulation processes and additives are also considered and suggestions made for future areas of research.

A pragmatic test of a simple calorimetric method for determining the fragility of some amorphous pharmaceutical materials.

PURPOSE: To evaluate a simple calorimetric method for estimating the fragility of amorphous pharmaceutical materials from the width of the glass transition region. METHODS: The glass transition temperature regions of eleven amorphous pharmaceutical materials were characterized at six different heating and cooling rates by differential scanning calorimetry (DSC). RESULTS: Activation energies for structural relaxation (which are directly related to glass fragility) were estimated from the scan rate dependence of the glass transition temperature, and correlations between the glass transition widths and the activation energies were examined. The expected correlations were observed, and the exact nature of the relationship varied according to the type of material under consideration. CONCLUSIONS: The proposed method of determining the fragility of amorphous materials from the results of simple DSC experiments has some utility, although "calibration" of the method for each type of materials is necessary. Further work is required to establish the nature of the relationships for a broad range of amorphous pharmaceutical materials.

Characteristics and significance of the amorphous state in pharmaceutical systems.

The amorphous state is critical in determining the solid-state physical and chemical properties of many pharmaceutical dosage forms. This review describes the characteristics of the amorphous state and some of the most common methods that can be used to measure them. Examples of pharmaceutical situations where the presence of the amorphous state plays an important role are presented. The application of our current knowledge to pharmaceutical formulation problems is illustrated, and some strategies for working with amorphous character in pharmaceutical systems are provided.

Inhibition of indomethacin crystallization in poly(vinylpyrrolidone) coprecipitates.

Differential scanning calorimetry and powder X-ray diffraction studies have been carried out with amorphous coprecipitates of indomethacin and poly(vinylpyrrolidone), PVP, to measure the glass transition temperature, Tg, as a function of mixture composition and the nonisothermal and isothermal crystallization of the indomethacin. Values of Tg as a function of mixture composition followed the ideal Gordon-Taylor equation up to about 50% w/w PVP. Inhibition of crystallization occurred at levels as low as 5% PVP and very significant inhibition was observed at and above 20% PVP. Inhibition of crystallization of indomethacin in the absence of PVP required a storage temperature 40-50 degrees C below Tg, whereas comparable inhibition with PVP was observed at storage temperatures 5 degrees C above Tg. This suggests that the inhibition of indomethacin crystallization by PVP may involve mechanisms other than just the general antiplasticizing effect (raising Tg) by PVP.

Molecular mobility of amorphous pharmaceutical solids below their glass transition temperatures.

PURPOSE: To measure the molecular mobility of amorphous pharmaceutical solids below their glass transition temperatures (Tg), using indomethacin, poly (vinyl pyrrolidone) (PVP) and sucrose as model compounds. METHODS: Differential scanning calorimetry (DSC) was used to measure enthalpic relaxation of the amorphous samples after storage at temperatures 16-47 K below Tg for various time periods. The measured enthalpy changes were used to calculate molecular relaxation time parameters. Analogous changes in specimen dimensions were measured for PVP films using thermomechanical analysis. RESULTS: For all the model materials it was necessary to cool to at least 50 K below the experimental Tg before the molecular motions detected by DSC could be considered to be negligible over the lifetime of a typical pharmaceutical product. In each case the temperature dependence of the molecular motions below Tg was less than that typically reported above Tg and was rapidly changing. CONCLUSIONS: In the temperature range studied the model amorphous solids were in a transition zone between regions of very high molecular mobility above Tg and very low molecular mobility much further below Tg. In general glassy pharmaceutical solids should be expected to experience significant molecular mobility at temperatures up to fifty degrees below their glass transition temperature.

Crystallization of indomethacin from the amorphous state below and above its glass transition temperature.

The solid state crystallization of amorphous polymers, sugars, and inorganic glasses is often thought to be restricted to the region above the glass transition temperature, Tg, because insufficient molecular mobility (high viscosity) exists below Tg for nucleation and crystal growth. Here we report on the isothermal and nonisothermal crystallization of dry amorphous indomethacin in the temperature range of 20 degrees C above and below its Tg. These studies were carried out with two amorphous samples having different degrees of metastability relative to the crystalline state. It was shown that in both samples significant crystallization to the most stable polymorphic form occurred over several days when stored below Tg, and in some cases this process was preceded by the relaxation of one amorphous form to the other. At storage temperatures near to and above Tg the rates of crystallization increased as expected but a second less thermodynamically stable polymorph also appeared with the more stable crystal form. This behavior was explained by the possible relationship between the degree of metastability relative to the crystalline state of each amorphous form and the interfacial energy existing at the respective nucleation sites, in accord with the Ostwald step rule.