Chemical mapping of hydration and dehydration process of theophylline in tablets using terahertz pulsed imaging

The purpose of this research is to investigate the topographical pattern of hydration and dehydration (also known as pseudo-polymorphic change) of drug substance in drug product using terahertz (THz) pulsed imaging. Emphasis is placed on (1) applicability of THz pulsed imaging and (2) kinetic analysis in the pseudo-polymorphic change. Either anhydrous or monohydrated form of theophylline was used as the drug substance, leading to initially anhydrous or monohydrated tablets. These tablets were stored at 25°C to keep the relative humidity constant at 84% (anhydrous tablets) or 45% (monohydrated tablets), respectively. The THz pulsed imaging was confirmed to enable visualization that the hydration of the anhydrous form or the dehydration of the monohydrated form began on the surface of the tablets and gradually progressed to the core side in the tablets with storage. Kinetic studies indicated that these pseudo-polymorphic changes followed the phase boundary mechanism. Since the other imaging techniques has been scarcely achieved to show the topographical pattern of pseudo-polymorphic change of drug substances in drug products directly and visually, it is considered that THz pulsed imaging has a potential ability to solve complicated issues in pharmaceutical development.     

Effects of dehydration temperatures on moisture absorption and dissolution behavior of theophylline.

Anhydrous theophylline was prepared by heating theophylline monohydrate at temperatures between 60 degrees C and 140 degrees C. The effects of dehydration temperatures on the moisture absorption and dissolution behavior of anhydrous theophylline were investigated in this study. The hydration rate of anhydrous theophylline at 95% relative humidity and 25 degrees C decreased with increasing dehydration temperatures. From the fitting analysis of solid-state reaction models, the hydration reaction was found to be governed by the phase boundary reaction model for samples prepared at lower dehydration temperatures (<100 degrees C) but the reaction obeyed the growth of nuclei reaction model when samples were dehydrated at higher temperatures. The dissolution rates of various anhydrous theophylline samples were measured by the rotating disk method. The calculated solubility of anhydrous theophylline prepared by heating was about 2.5 times higher than that of theophylline monohydrate. The phase transformation rate from the anhydrous form to the monohydrate during dissolution tests decreased with higher dehydration temperatures. It was found that the anhydrous theophylline prepared at different dehydration temperatures transformed to the monohydrate by way of different growth of hydrate nuclei mechanism.     

Vibrational spectra of anhydrous and monohydrated caffeine and theophylline molecules and crystals

Density functional theory and classical molecular dynamics simulations are used to investigate the vibrational spectra of caffeine and theophylline anhydrous and monohydrate molecules and those of their crystalline anhydrous and monohydrated states, with emphasis in the terahertz region of the spectra. To better understand the influence of water in the monohydrate crystal spectra, we analyze the vibrational spectra of water monomer, dimer, tetramer, and pentamer, and also those of liquid water at two different temperatures. In small water clusters, we observe the progressive addition of translational and librational modes to the terahertz region of the spectra. The water spectra predicted by rigid and flexible water models is examined with classical molecular dynamics, and the respective peaks, especially in the terahertz region, are compared with those found in the small clusters. Similar analysis done for caffeine and theophylline monohydrate molecules using density functional theory clearly shows the presence of water modes in the librational states and in the water stretching region. Molecular dynamics of caffeine and theophylline anhydrous and monohydrate crystals reveal the influence of vibrations from the molecule-molecule (caffeine or theophylline) crystal stacks and those from the water-molecule interactions found in the monohydrate molecules and new modes from molecule-molecule, water-molecule, and water-water hydrogen bonding interactions arising from collective effects in the crystal structure. Findings illustrate challenges of terahertz technology for the detection of specific substances in condensed phases.     

Construction of a naproxen ion-selective electrode and its application to pharmaceutical analysis

A naproxenate-selective electrode with a liquid membrane consisting of a tetraheptylammonium-naproxenate ion pair dissolved in p-nitrocumene is described. The electrode exhibits a rapid and near-Nernstian response to naproxenate activity from 10(-1) to 10(-4) M at pH 9.0 (borate buffer). No serious interference from common ions and tablet excipients was found and the electrode was used for the direct assay of naproxen tablets by means of the calibration graph technique and of suppositories using the standard additions technique. A dissolution study of naproxen tablets was also carried out and the results compared favourably with those given by the USP XXI methods.     

Simultaneous determination of theophylline and caffeine by proton magnetic resonance spectroscopy using partial least squares regression techniques.

A 1H-NMR procedure based on an analysis of its data by a multivariate calibration method was conducted for the simultaneous determination of theophylline and caffeine in synthetic and real samples. Partial least squares regression (PLS) was chosen as the calibration method. The methyl signals of theophilline at 3.36 and 3.54 ppm that overlapped with those of caffeine were significant characteristics which were employed in this study for their analyses. The proposed method was successfully applied to recovery studies of theophylline and caffeine from real tablet samples.     

Abnormal dissolutions of chlorpromazine hydrochloride tablets in water by paddle method under a high agitation condition

All sugar-coated tablets of chlorpromazine hydrochloride except for those produced by one manufacture showed concave dissolution profiles in water by paddle method at 100 rpm but not at 50 rpm. The study was undertaken to clarify the agitation-dependent abnormal dissolutions. The strange dissolutions were also observed in water at different ionic strengths but not in buffer solutions of pH 1.2, 4.0 and 6.8. When monitored, the pH's of water in dissolution vessels for the abnormal tablets increased with time at 100 rpm and some of them exceeded pH 8 but did not at 50 rpm. The solubility of chlorpromazine hydrochloride decreased with the increase of pH which was too low to dissolve the whole amount of drug contained in a tablet at pH 8. The elevation of pH seemed to be mainly brought about by dissolution of calcium carbonate popularly used for sugar-coated tablets, because larger amount of calcium ion was dissolved out from the abnormal tablets at 100 rpm than from a normal tablet and from them at 50 rpm. These findings indicate that the concave dissolution profiles should be caused by the decrease of drug solubility with increase in pH of water, probably because of dissolution of calcium carbonate. We should pay attention to the change in pH of water which may differ depending on the agitation speed of dissolution tests.     

Predicting the drug concentration in starch acetate matrix tablets from ATR-FTIR spectra using multi-way methods

The amounts of drug and excipient were predicted from ATR-FTIR spectra using two multi-way modelling techniques, parallel factor analysis (PARAFAC) and multi-linear partial least squares (N-PLS). Data matrices consisted of dissolved and undissolved parallel samples having different drug content and spectra, which were collected at axially cut surface of the flat-faced matrix tablets. Spectra were recorded comprehensively at different points on the axially cut surface of the tablet. The sample drug concentrations varied between 2 and 16% v/v. The multi-way methods together with ATR-FTIR spectra seemed to represent an applicable method for the determination of drug and excipient distribution in a tablet during the release process. The N-PLS calibration method was more robust for accurate quantification of the amount of components in the sample whereas the PARAFAC model provided approximate relative amounts of components.     

Preparation and evaluation of tablets rapidly disintegrating in saliva containing bitter-taste-masked granules by the compression method.

The aim of this study was to prepare, using taste-masked granules, tablets which can rapidly disintegrate in saliva (rapidly disintegrating tablet), of drugs with bitter taste (pirenzepine HCl or oxybutynin HCl). The taste-masked granules were prepared using aminoalkyl methacrylate copolymers (Eudragit E-100) by the extrusion method. None of the drugs dissolved from the granules (% of dissolved, < 5%) even at 480 min at pH 6.8 in the dissolution test. However, the drugs dissolved rapidly in the medium at pH 1.2 in the dissolution test. Rapidly disintegrating tablets were prepared using the prepared taste-masked granules, and a mixture of excipients consisting of crystalline cellulose (Avicel PH-102) and low-substituted hydroxypropylcellulose (L-HPC, LH-11). The granules and excipients were mixed well (mixing ratio by weight, crystalline cellulose: L-HPC = 8:2) with 1% magnesium stearate, and subsequently compressed at 500-1500 kgf in a single-punch tableting machine. The prepared tablets (compressed at 500 kgf) containing the taste-masked granules have sufficient strength (the crushing strength: oxybutynin tablet, 3.5 kg; pirenzepine tablet, 2.2 kg), and a rapid disintegration time (within 20 s) was observed in the saliva of healthy volunteers. None of the volunteers felt any bitter taste after the disintegration of the tablet which contained the taste-masked granules. We confirmed that the rapidly disintegrating tablets can be prepared using these taste-masked granules and excipients which are commonly used in tablet preparation.     

Application of nilvadipine solid dispersion to tablet formulation and manufacturing using crospovidone and methylcellulose as dispersion carriers

Nilvadipine (NIL) solid dispersion using crospovidone (Cross-linked-N-vinyl-2-pyrolidone, cl-PVP) and methylcellulose (MC) as carriers was applied to tablet formulation. Several grades of cl-PVP and MC were used, and their influence on tablet properties such as hardness, disintegration, dissolution and chemical stability were investigated. The agitation granulation method was used for preparation of solid dispersion granules, and the granules were compressed using a rotary tableting machine, and finally the obtained tablets were coated with film. As the particle size of cl-PVP decreased, hardness and apparent solubility were increased, while dissolution rate was lowered. When a higher viscosity grade of MC was used, hardness and dissolution rate were increased, and apparent solubility did not change. All batches of tablets were chemically stable at 40 degrees C, 75% relative humidity (R.H.) for six months. Finally, tablets with enhanced dissolution properties were obtained by using Polyplasdone XL-10 and Metolose SM-25 as the grades of cl-PVP and MC, respectively. These formulation tablets showed higher solubility and dissolution rate during storage as well as initial indicating good physical stability.     

Simultaneous Determination of Two Antibiotics in Tablets by Spectrophotometry and Principal Component Regression (PCR) Analysis. An Advanced Undergraduate Experiment Involving Chemometrics

An advanced analytical chemistry laboratory experiment involving the simultaneous determination of the antibiotics sulfamethoxazole and trimethoprime in commercial tablets is described. It involves the following steps: (1) preparation of nine calibration mixtures and the recording of their absorption spectra in the region 200–320 nm, (2) dissolution of the tablet contents and the recording of spectrophotometrics data, and (3) processing the data with the multivariate calibration technique of principal component regression (PCR). The theory of PCR is discussed, and a Visual Basic program is made available for data processing. The latter program allows students to obtain and save relevant statistical information (root-mean-square deviation, correlation coefficient, and relative error of prediction), as well as calibrate spectral factors and spectral residuals for each test sample. This program helps to illustrate the PCR technique in detail. The reagents used are of low cost and nontoxic; the experiment is simple and provides students with insight into a the real practice of integrating chemistry, instrumentation and computer techniques.     

Application of transmission near-infrared spectroscopy to uniformity of content testing of intact steroid tablets

Transmission near-infrared (NIR) spectroscopy was used for the rapid and non-destructive determination of the content of a hormone steroid in single intact tablets. Tablets produced for clinical trial purposes containing 5, 10, 15, 20 and 30 mg (2.94, 5.88, 8.82, 11.76 and 17.64% m/m, respectively) were used to develop calibration models without the need to specially prepare any out of specification tablets. Reference values for the individual tablets used in the NIR calibration models and test set were measured by reversed-phase high performance liquid chromatography (HPLC). Partial least squares regression using standard normal variate transformed second-derivative spectra over the range 800 to 1040 nm gave the optimum calibration model with a standard error of calibration of 0.52 mg per tablet. Measurements of an independent test set gave comparable results (standard error of prediction 0.31 mg per tablet). Measurement errors for a single tablet (RSD < 2.5% for a given active level) were sufficiently small to allow the procedure to be applied to pharmacopoeial uniformity of content testing of batches of these tablets and permitted the non-destructive testing of 30 tablets in under 20 min as compared to 6 h by HPLC.     

Immediate release tablets of telmisartan using superdisintegrant-formulation, evaluation and stability studies

Telmisartan (anti-hypertensive) is insoluble in water; hence the drug may be slowly or incompletely dissolved in the gastro intestinal tract. So the rate of dissolution and therefore its bioavailability is less (bioavailability 42%). In the present study an attempt has been made to prepare immediate release tablets of telmisartan by using Polyplasdone XL-10 (Crosspovidone) at intragranular, extragranular and partly intra and extragranular level of addition to increase the rate of drug release from dosage form to increase the dissolution rate and hence its bioavailability. The prepared granules and tablets were evaluated for their physiochemical properties and in-vitro dissolution study was conducted for the prepared tablets. It was concluded that the immediate release tablets with proper hardness, disintegration time and with increase rate of dissolution can be made using Polyplasdone XL-10. Formuation-10 (F10) was selected for stability study and the in-vitro dissolution study showed that was no difference in percent of drug released between initial and sixth month sample.     

Tabletting of solid dispersion particles consisting of indomethacin and porous silica particles

We attempted to make the rapidly dissolving tablet (Tab) containing solid dispersion particles (SD) with indomethacin (IMC) and porous silica (Sylysia350) as carrier prepared by using spray-drying technique. Rapidly dissolving tablet was formulated with mannitol as a diluent and low substituted hydroxypropylcellulose (L-HPC) or partly pre-gelatinized starch (PCS) as a disintegrant. The percent dissolved from Tab (SD) was higher than that of tablet containing physical mixture (PM) at 20 min. Nearly 100% of drug in Tab (SD) was dissolved within 60 min, while the drug dissolution of Tab (PM) was not completed at the same time period. In addition, the tensile strength of Tab (SD) was much higher than that of Tab (PM). Adding L-HPC in Tab (SD) (Tab (SD-L-HPC)), the percent dissolved from Tab (SD-L-HPC) at 5 min became much higher than that from Tab (SD). The dissolution profile of IMC from Tab (SD-L-HPC) was almost the same irrespective of the compression pressure, while the tensile strength of tablet increased with increasing the compression pressure. In comparing the compaction property of these tablets by observing the ratio of residual die wall pressure (RDP) to maximum die wall pressure (MDP) (RDP/MDP), it was found that addition of L-HPC in the tablet formulation improved compactibility. In case that PCS was formulated as disintegrant, Tab (SD-PCS), similar improvement in the dissolution profile and tensile strength was observed, though the dissolution rate of IMC from Tab (SD-PCS) was slightly lower than that from Tab (SD-L-HPC) irrespective of the compression pressure.     

Nano- and macro-geometrical structural change of caffeine and theophylline anhydrate tablets during hydration process by using X-ray computed tomography

The effects of nano- and macro-geometrical factors on the hydration kinetics of caffeine (CA) and theophylline anhydrate (TA) tablets at high humidity were investigated using X-ray high-resolution computed tomography (CT). Hydration profiles of CA and TA tablets obtained at 25 and 50 MPa, 96% relative humidity, and 20 °C were measured by weight and X-ray CT. The total tablet volume (G-V) and average tablet density (G-D) calculated based on the volume and weight of tablets, and tablet volume (CT-V) and tablet density (CT-D) were evaluated by X-ray CT. The hydration kinetics of CA and TA tablets followed two-dimensional growth of nuclei (Avrami-Erofee) and three-dimensional phase boundary equations, respectively. The increase in the G-V of TA tablets was initially more than, but later less than, that of CA tablets. The G-D of CA tablets varied extensively and was constant initially, whereas that of TA tablets decreased significantly in the initial stage. The CT-V of CA tablets gradually increased initially, but that of TA tablets increased significantly early on. The inter-granular volume (IG-V) of both tablets decreased initially with large fluctuations, but then increased. The CT-D of CA tablets decreased significantly, but that of TA tablets did not decrease. The hydration kinetics of CA and TA tablets was affected by changes in the geometrical structure of the tablets. X-ray CT is a powerful tool for evaluating dynamic changes inside tablets.     

Theoretical analysis of tablet hardness prediction using chemoinformetric near-infrared spectroscopy.

In order to clarify the theoretical basis of the variability in the measurement of tablet hardness by compression pressure, NIR spectroscopic methods were used to predict tablet hardness of the formulations. Tablets (200 mg, 8 mm in diameter) consisting of berberine chloride, lactose, and potato starch were formed at various compression pressures (59, 78, 98, 127, 195 MPa). The hardness and the distribution of micropores were measured. The reflectance NIR spectra of various compressed tablets were used as a calibration set to establish a calibration model to predict tablet hardness by principal component regression (PCR) analysis. The distribution of micropores was shifted to a smaller pore size with increasing compression pressure. The total pore volume of tablets decreased as the compression pressure increased. The hardness increased as the compression pressure increased. The hardness could be predicted using a calibration model consisting of 7 principal components (PCs) obtained by PCR. The relationship between the predicted and the actual hardness values exhibited a straight line, an R(2) of 0.925. In order to understand the theoretical analysis (scientific background) of calibration models used to evaluate tablet hardness, the standard error of cross validation (SEV) values, the loading vectors of each PC and the regression vector were investigated. The result obtained with the calibration models for hardness suggested that the regression vector might involve physical and chemical factors. In contrast, the porosity could be predicted using a calibration model composed of 2 PCs. The relationship between the predicted and the actual total pore volume showed a straight line with R(2) = 0.801. The regression vector of the total pore volume might be due to physical factors.     

Pharmacokinetics of a new sustained-release formulation of theophylline sodium glycerinate in healthy subjects with a new asymmetric dosage regimen

Pharmacokinetics of a new sustained-release formulation of theophylline sodium glycerinate in healthy subjects was studied. In this study, a new asymmetric dosage regimen was presented to achieve a better accordance with the chronotherapy of asthma. Each of 10 subjects was administered one tablet (equivalent to 0.1 g anhydrous theophylline) in the morning and four tablets in the evening for a consecutive 6 days and blood samples were collected at the predetermined time and analyzed by a validated HPLC method. This new regimen produced a steady and effective level of theophylline in plasma for the whole day, especially in the evening. A lower dose in the morning could reach the effective level (C(min)4.97 +/- 1.60 microg/mL and C(max)10.68 +/- 1.80 micro g/mL over the a.m. dosing interval) and a higher dose in the evening did not result in toxic levels but led to a reasonable concentration range (C(max)9.72 +/- 1.56 microg/mL over p.m. dosing interval), which could maintain a higher plasma theophylline concentration without the risk of serious adverse events and control asthmatic symptoms probably occurring during the night or early in the morning. The results suggested that the proposed asymmetric regimen was necessary, practicable and safe for twice daily sustained-release tablets of theophylline sodium glycerinate and also provides the basis for the clinical dosage regimen of other theophylline formulated products.     

Stabilization mechanism of clarithromycin tablets under gastric pH conditions

It has been reported that tablets of clarithromycin (CAM), a 14-membered macrolide antibiotic, are especially stable under low pH conditions such as in gastric fluid, and showed excellent antibacterial efficiency even though CAM molecules themselves are rapidly decomposed. Therefore, we aimed to clarify the stabilization mechanism of CAM tablets under low pH conditions. From the results of stability and dissolution tests, the optimal decomposition rate constant (K(dec)) and dissolution rate constant (K(dis)) at various pH values were calculated by curve-fitting to consecutive reactions. Consequently, log(K(dec)) increased as pH decreased. On the other hand, log(K(dis)) increased as pH decreased from 3.0 to 1.5, but decreased as pH decreased from 1.5 to 1.0. In addition, the disintegration time of commercially available tablets at pH 1.0 and 1.2 was found to be delayed, resulting in a decrease of K(dis). Furthermore, from powder X-ray diffraction, HPLC and elemental analysis, the delay in disintegration time might be attributable to the formation of a transparent gel, formed by the reaction between CAM molecule and hydrochloric acid under low pH conditions, on the surface of CAM tablet. On the basis of these results, this report can be considered the first case where a transparent gel prevents gastric fluid from penetrating the tablet, resulting in reduced decomposition of CAM following oral administrating.     

Sodium mefenamate as a solution for the formulation and dissolution problems of mefenamic acid

Sodium salt formation of mefenamic acid (MA) was studied as a way to solve the formulation and dissolution problems of MA. For this purpose, sodium salt of mefenamic acid (Na-MA) was prepared by reacting MA powder with equimolar sodium hydroxide in an aqueous phase, and consequently, Na-MA solution was obtained. The resultant solution was lyophilized and Na-MA powder was collected. The salt formation was confirmed by the results of fourier transformation-infrared (FTIR) spectroscopy and differential scanning calorimetry (DSC) studies on Na-MA powder in comparison to MA powder. Na-MA powder was assessed for direct compressibility, in comparison to MA powder, when formulated as a mixture with minimum amount of Avicel((R)) pH 101 and then compressed into tablets using a hydraulic tablet press. Na-MA tablets exhibited satisfactory hardness and friability, and did not show capping or lamination. On the other hand, some MA tablets showed capping or lamination upon compression and all the tested MA tablets for friability capped. Na-MA tablets were also studied for drug dissolution, in comparison to MA tablets, in water, a pH 7.4 phosphate buffer, and a pH 7.4 phosphate buffer after soaking in 0.1 m HCl. Under these different dissolution conditions, Na-MA tablets showed much higher dissolution rate and extent than MA tablets. The results of the study suggested that Na-MA can be considered as a solution form for the formulation and dissolution problems of MA.     

Controlled release from directly compressible theophylline buccal tablets

The aim of the current study was the development of theophylline buccal adhesive tablets using direct compression. Buccal adhesive formulations were developed using a water soluble resin with various combinations of mucoadhesive polymers. The prepared theophylline tablets were evaluated for tensile strength, swelling capacity and ex vivo mucoadhesion performance. Ex vivo mucoadhesion was assessed using porcine gingival tissue and the peak detachment forces were found to be suitable for a buccal adhesive tablet with a maximum of 1.5 N approximately. The effect of formulation composition on the release pattern was also investigated. Most formulations showed theophylline controlled release profiles depended on the grade and polymer ratio. The release mechanisms were found to fit Peppas’ kinetic model over a period of 5 h. In general the majority of the developed formulations presented suitable adhesion and controlled drug release.     

Some physical properties of tabletted seed of Garcinia kola (HECKEL)

The formulation of Garcinia kola seeds into tablet dosage form and evaluation of some physical properties of the tablets are presented. A chemical assay was conducted on the dry, powdered seeds as well as the crude aqueous extract of the seeds. The dry powdered seeds contain 0.003% of flavonoids while the crude extract contained 0.007% of flavonoids based on rutin used as the standard. The powdered material (50 mg) and crude extract (10 mg) were formulated into tablets using the wet granulation method. Named binders were evaluated in these formulations. The various tablet parameters were evaluated, namely: weight variation, thickness and diameter, hardness, friability, disintegration time, dissolution profile and content uniformity. The results indicated that the tablets had good disintegration time, dissolution and hardness/friability profiles. Tablets formulated with starch had the best disintegration properties but were consequently very friable. Tablets formulated from 10 mg of the crude extract needed a larger proportion of diluents, which affected the tablet properties.