Intact Tablets Research Articles

Dissolution of Intact, Divided and Crushed Circadin Tablets: Prolonged vs. Immediate Release of Melatonin.

Circadin 2 mg prolonged-release tablet is the only licensed melatonin product available in the UK. Circadin is indicated for patients with primary insomnia aged 55 and over, but is more widely used “off-label” to treat sleep disorders especially in the paediatric population. Children and older people often have difficulty swallowing tablets and dividing the tablet is sometimes required to ease administration. The aim of this study was to measure the release profile of melatonin from Circadin tablets when divided or crushed, and compare this with release from intact tablets. Dissolution testing was also performed for unlicensed melatonin products for comparison. Dissolution tests were performed using the pharmacopoeial paddle apparatus, with melatonin release analyzed by high performance liquid chromatography. Melatonin content, hardness, friability, and disintegration of the products were also evaluated. The prolonged release of melatonin from Circadin tablets was unlike that of any other product tested. When divided into halves, Circadin preserved most of the prolonged-release characteristic (f2 = 58), whereas quarter-cut and crushed tablet had a more immediate melatonin release profile. Circadin is significantly less expensive and should be preferred to unlicensed medicines which are not pharmaceutically equivalent and offer less quality assurance.

Calibration transfer from powder mixtures to intact tablets: A new use in pharmaceutical analysis for a known tool

Calibration transfer is commonly used for spectra obtained in different spectrometers or other conditions. This paper proposed the use of calibration transfer between spectra recorded for the same samples in different physical forms. A new method was developed for the direct determination of nevirapine in solid pharmaceutical formulations based on diffuse reflectance near infrared spectroscopy (NIRS) and partial least squares (PLS). This method was developed with 50 powder mixtures and then, successfully extended to the quantification in intact tablets by using calibration transfer with double window piecewise direct standardization (DWPDS). This chemometric strategy provided good results with a small number of tablet transfer samples, only seven, prepared out of the narrow range of active principle ingredients (API) content around the nominal value of the formulation (100%). The method was fully validated in the working range of 83.0–113.9% of nevirapine and the use of DWPDS allowed to significantly decreasing the root mean square error of prediction (RMSEP) from 4.8% (tablets predicted by a model built with only powder samples) to 2.6%. The range of relative errors decreased from −5.1/8.7% to −4.6/3.3%. Considering that the amount of raw materials demanded for preparing tablets is up to ten times higher than for powder mixtures, this type of application is of particular interest in pharmaceutical analysis. In the context of process analytical technology (PAT), the use of the same multivariate model in different steps of the production is very advantageous, saving time and labor.

New Easily Swallowed Tablets with Slippery Coating for the Antihypertensive Drug Valsartan

Different tablet dosage forms were prepared to be administered for patients with dysphagia (swallowing difficulties) like buccal, sublingual and orodispersible tablets, however, they possesses certain constrains like taste masking difficulties, limitations in drug and dose selection and friability. Hence, in an attempt to overcome these constrains, a new easily swallowed immediate release tablets containing (160mg) Valsartan were prepared, and designed to be slippery upon contact with saliva giving an easy swallowing of the intact tablet (without water) with efficient taste masking effect, thus, they called Oroslippery tablets (OSTs). Core tablets were prepared by direct compression using different superdisintegrants, followed by dipping in special coating dispersion containing different proportion of kollicoat IR (film former) and xanthan gum (slipperiness inducer) at different coating levels. These OSTs were optimized for their physical properties, in-vitro disintegration and release in addition to in-vivo slipperiness and taste masking effect. It was found that F12 containing 6% crosscarmellose sodium double coated with 15% kollicoat IR and 0.3% xanthan gum possessed a good mechanical strength (hardness=5.69±0.58 Kg/cm2, friability=0.09%±0.79), suitable in-vivo slipperiness and taste masking times (8±1.45 and 58±2.18 seconds) respectively, with longer disintegration time (5.57±1.36 minutes) but similar release profile to the commercial conventional tablet Diovan® with similarity factor (f2= 68.4±1.07) and difference factor (f1= 1.39± 0.95). Therefore, this study developed a new easily swallowed tablet with an efficient taste masking property, high loading capacity and adequate mechanical strength that can be used as an alternative to buccal, sublingual and orodispersible tablets.

Tailoring a Pediatric Formulation of Artemether-Lumefantrine for Treatment of Plasmodium falciparum Malaria.

Specially created pediatric formulations have the potential to improve the acceptability, effectiveness, and accuracy of dosing of artemisinin-based combination therapy (ACT) in young children, a patient group that is inherently vulnerable to malaria. Artemether-lumefantrine (AL) Dispersible is a pediatric formulation of AL that is specifically tailored for the treatment of children with uncomplicated Plasmodium falciparum malaria, offering benefits relating to efficacy, convenience and acceptance, accuracy of dosing, safety, sterility, stability, and a pharmacokinetic profile and bioequivalence similar to those of crushed and intact AL tablets. However, despite being the first pediatric antimalarial to meet World Health Organization (WHO) specifications for use in infants and children who are ≥5 kg in body weight and its inclusion in WHO Guidelines, there are few publications that focus on AL Dispersible. Based on a systematic review of the recent literature, this paper provides a comprehensive overview of the clinical experience with AL Dispersible to date. A randomized, phase 3 study that compared the efficacy and safety of AL Dispersible to those of crushed AL tablets in 899 African children reported high PCR-corrected cure rates at day 28 (97.8% and 98.5% for AL Dispersible and crushed tablets, respectively), and the results of several subanalyses of these data indicate that this activity is observed regardless of patient weight, food intake, and maximum plasma concentrations of artemether or its active metabolite, dihydroartemisinin. These and other clinical data support the continued use of pediatric antimalarial formulations in all children <5 years of age with uncomplicated malaria when accompanied by continued monitoring for the emergence of resistance.

Human abuse potential of immediate-release/extended-release versus immediate-release hydrocodone bitartrate/acetaminophen: a randomized controlled trial in recreational users of prescription opioids

Background. The abuse potential of prescription opioids is well established. This study compared positive, subjective drug effects of single, equal doses of biphasic immediate release (IR)/extended release (ER) hydrocodone bitartrate (HB)/acetaminophen (acetyl-p-aminophenol [APAP]) 7.5/325 mg tablets versus IR HB/APAP 7.5/325-mg tablets and placebo. Methods: Healthy adult recreational users of prescription opioids entered this randomized, double-blind, double-dummy, active- and placebo-controlled, seven-way crossover study. Participants received single, total doses of IR/ER HB/APAP 22.5/975 mg (intact; three active tablets) and 45/1950 mg (intact and crushed [encapsulated]; six active tablets), IR HB/APAP 22.5/975 mg (intact; three active tablets) and 45/1950 mg (intact and crushed [encapsulated]; six active tablets), and placebo. Peak subjective effects (Emax); time to peak effects (TEmax); and area under the drug–effect curves for drug liking, high, and good drug effects were measured using visual analog scales. Median values with 95% confidence interval (CI) were compared using analysis of variance. Results: Among completers (n = 52), IR/ER HB/APAP produced delayed and lower peak effects compared to equal doses of IR HB/APAP. Comparing intact tablets, the drug liking Emax (median [95% CI]) was significantly lower for IR/ER HB/APAP 45/1950 mg (78.0 [73.0, 81.0]) than an equal dose of IR HB/APAP (89.5 [85.0, 93.0]; difference, –8.5 [–12.0, –6.0]; P < 0.001). Similar results were observed for intact IR/ER HB/APAP and IR HB/APAP 22.5/975 mg. Crushing IR/ER HB/APAP 45/1950 mg delayed these effects compared with an equal dose of crushed IR HB/APAP and intact IR/ER HB/APAP. Conclusion. IR/ER HB/APAP resulted in lower subjective positive drug effects than an equal dose of IR HB/APAP. Crushing IR/ER HB/APAP also delayed the onset of subjective effects compared with intact IR/ER HB/APAP. These findings suggest that biphasic IR/ER HB/APAP has lower abuse potential than IR HB/APAP in single equal doses. Registration: This Phase I clinical trial conducted in the USA was not registered.

Evaluation of Rapidly Disintegrating Vaginal Tablets of Tenofovir, Emtricitabine and Their Combination for HIV-1 Prevention.

Vaginal tablets are being developed as an alternative to gels as an inexpensive, discreet dosage form for the administration of microbicides. This work describes the pharmacokinetic (PK) evaluation of rapidly disintegrating vaginal tablets containing tenofovir (TFV, 10 mg), emtricitabine (FTC, 10 mg), and the combination of TFV and FTC (10 mg each) under in vitro and in vivo conditions, and in direct comparison to the clinical TFV 1% gel, a microbicide product in Phase III clinical testing. The PK of TFV and FTC from tablets were also evaluated in female rabbits following intravaginal administration. Direct comparison of a single dose of TFV tablets (intact or predissolved at 10 mg/mL) and TFV 1% gel showed no differences in the vaginal PK of TFV between groups; however systemic bioavailability of TFV was significantly higher from the gel. When rabbits were dosed either once or daily for seven days with intact tablets of TFV, FTC, or the combination of TFV/FTC, vaginal and systemic concentrations of TFV and FTC were unaffected by co-formulation. Moreover, plasma PK parameters were similar following a single dose or seven once-daily doses. Tissue concentrations of TFV and FTC in the cranial vagina 4 h after administration ranged between 104 and 105 ng/g. Concentrations of TFV-diphospate (TFV-DP, the active metabolite) were also high (over 103 ng/g or about 3000 to 6000 fmol/mg) in the cranial vagina 4 h after administration and similar to those measured following administration of TFV 1% gel. These data demonstrate that rapidly disintegrating vaginal tablets may be a suitable topical microbicide dosage form providing similar vaginal TFV PK to that of TFV 1% gel. The data also support co-administration of FTC with TFV in a single vaginal tablet to create a combination microbicide in a simple and inexpensive dosage form.

Stability and recovery of DIFICID(®) (Fidaxomicin) 200-mg crushed tablet preparations from three delivery vehicles, and administration of an aqueous dispersion via nasogastric tube.

Fidaxomicin is approved for the treatment of adults with Clostridium difficile–associated diarrhea, many of whom have difficulty swallowing an intact tablet. The study objective was to evaluate the stability and recovery of crushed DIFICID® (fidaxomicin) 200-mg tablets dispersed in water, applesauce, or Ensure® brand liquid nutritional supplement, and to determine the recovery of fidaxomicin from the administration of an aqueous dispersion of a crushed DIFICID® tablet through a nasogastric (NG) tube. DIFICID® tablets were crushed and dispersed in water, applesauce, or Ensure®. The stability and recovery of fidaxomicin were evaluated over 24 h in these vehicles. In a separate experiment, the ability to recover a full dose of fidaxomicin when administering as an aqueous dispersion through an NG tube was assessed. When DIFICID® tablets were crushed and dispersed in water, the active ingredient, fidaxomicin, was stable for up to 2 h at room temperature. Additionally, it was stable for up to 24 h in dispersions with applesauce or Ensure®. Recovery of fidaxomicin after crushing and dispersing in any of the three vehicles studied ranged from 95 to 108 %, which is within the normal range of individual tablet variability. When crushed, dispersed in water, and administered through an NG tube, the average recovery of fidaxomicin was 96 %. Stability and recovery of fidaxomicin were confirmed when DIFICID® tablets were crushed and dispersed in water, applesauce, or Ensure®. In addition, administration of an aqueous dispersion of a crushed tablet through an NG tube is supported by acceptable recovery of fidaxomicin.

Effect of simulated precompression, compression pressure and tableting speed on an offline diffuse transmittance and reflectance near-infrared spectral information of model intact caffeine tablets

Near-infrared spectroscopy (NIRS) is used in the pharmaceutical industry for monitoring drug content during the tablet manufacturing process. It is of critical importance to understand the effect of process factors on NIRS performance. Design of Experiments (DoE) methodology was applied in this work for the systematic study of the effects of compression pressure, precompression pressure and tableting speed on an average Euclidean distance (AED), which reflects spectral features of the tablets, and root mean-squared error of prediction (RMSEP) as key performance indicator of NIRS calibration models. Caffeine tablets were manufactured in 17 experimental runs in accordance with D-optimal design. Developed diffuse transmittance (DT) and diffuse reflectance (DR) calibration models were tested on five independent test sets to confirm the conclusions of the DoE. Compression pressure and tableting speed have shown significant effect on the studied responses in DT mode, whereas all three studied factors have shown a significant effect in DR mode. Significant factors were considered in the development of the global calibration models. The authors suggest further study of RMSEP and AED responses to draw reliable conclusions on the effects of tableting process factors. The global calibration model in DT mode has shown superior performance compared to DR mode.

Comparison of Subjective Effects of Extended-Release Versus Immediate-Release Oxycodone/Acetaminophen Tablets in Healthy Nondependent Recreational Users of Prescription Opioids: A Randomized Trial

Background: Prescription opioids have substantial abuse potential. This study compared the positive subjective drug effects of a newly developed extended-release (ER) oxycodone (OC)/acetaminophen (acetyl-para-aminophenol [APAP]) formulation with those of immediate-release (IR) OC/APAP. Methods: This randomized, double-blind, active- and placebo-controlled, 7-way crossover study enrolled healthy volunteers who were recreational prescription opioid users. The protocol was approved by an institutional review board and all participants provided written informed consent. Participants received single doses of intact ER and IR OC/APAP 15/650 mg, intact ER and IR OC/APAP 30/1300 mg, crushed ER and IR OC/APAP 30/1300 mg, and placebo. Peak subjective effects (Emax), time to Emax, and area under the drug-effect curves for drug liking, drug high, and good drug effects were measured using visual analogue scales. Least squares means with 95% confidence interval were compared using analysis of variance. Results: Among completers (N = 55), intact ER OC/APAP produced delayed and lower peak effects versus IR OC/APAP. Comparing intact tablets, the drug liking Emax (least squares means [95% confidence interval]) was significantly lower for OC/APAP 30/1300 mg (76.4 [72.8 to 80.0]) than for IR OC/APAP 30/1300 mg (85.6 [81.9 to 89.2]; difference, −9.2 [−13.1 to −5.2]; P < 0.001). Similar results were observed for intact ER and IR OC/APAP (15 mg/650 mg). Crushing ER OC/APAP 30/1300 mg further delayed these effects compared with the same dose of crushed IR OC/APAP and intact ER OC/APAP. Conclusions: Extended-release OC/APAP produced lower subjective drug effects than IR OC/APAP. Crushing ER OC/APAP further delayed onset of subjective effects compared with intact ER OC/APAP. The ER OC/APAP may be less attractive for abuse than IR OC/APAP. Clinical trial registration: This phase 1 study conducted in the United States was not registered.

Towards a real time release approach for manufacturing tablets using NIR spectroscopy

The aim of this study was to use the near-infrared spectroscopy (NIRS) as a process analytical tool to evaluate the conformity of paracetamol tablets in terms of four Pharmacopoeia tests (content uniformity, hardness, disintegration time, friability) and to control in-line blend uniformity.Tablets were manufactured by direct compression. Three different active pharmaceutical ingredient (API) concentrations were manufactured and three different compaction pressures were used. Intact tablets were analysed by transmission mode with NIRS prior to European Pharmacopoeia tests that were used as reference methods.Partial least square (PLS) regression was selected to build the prediction NIR models for content uniformity, tablet hardness and disintegration time. The prediction of NIR content uniformity and tablet hardness methods were validated using the accuracy profile approach. The values of the root mean squared error of calibration (RMSEC) and the root mean squared error of prediction (RMSEP) for the disintegration time indicated the robustness and the global accuracy of the NIR model. Regarding the tablet friability test, the classification was based on K-nearest neighbours (KNN).Then tablet NIR analyses successfully allowed the prediction of their conformity. Compared to the time consuming Pharmacopoeia reference methods, the benefit of this nondestructive method is significant, especially for reducing batch release time.

Effect of acid modification on the material and compaction properties of fonio and sweet potato starches

Starches obtained from the grains of white fonio (Digitaria exilis) and tubers of sweet potato (Ipomea batatas) have been modified by acid hydrolysis at different steeping times – (0, 24 and 96 h) and the physicochemical, material and compaction properties of the modified starches have been evaluated in comparison with official corn starch. The effect of acid modification on the compaction properties of the starches were evaluated with the aim of determining their usefulness as excipients in direct compression. The results showed that the physicochemical and material properties of the starches varied considerably depending on their botanical source. Acid modification led to an increase in solubility and relative crystallinity but decrease in swelling and viscosity of the starches. The effects were found to depend on the steeping time during acid hydrolysis. The results of the compressional properties indicated that the starches formed intact tablets at relatively low compression pressure with acid modified starches forming tablets with higher tensile strength than the natural starches. The results indicate that the physicochemical and compaction properties of white fonio and sweet potato starches were improved by acid modification yielding starches that could be suitable as directly compressible excipient.

Tu1113 Dexlansoprazole Modified-Release Orally-Disintegrating Tablet -The Bioavailability of Alternate Dosing Options

Introduction: The proton pump inhibitor dexlansoprazole (DEX) is a modified release (MR) formulation consisting of 2 types of granules within a single capsule. DEX delayed-release capsules are approved for use in adults for treatment of heartburn associated with symptomatic nonerosive gastroesophageal reflux disease, healing of erosive esophagitis (EE), and maintenance of healed EE and relief of heartburn. Because some patients are unable or unwilling to swallow capsules, a DEX MR orally-disintegrating (OD) tablet has been developed. DEX MR OD contains 2 types of granules that release drug in a pH-dependent manner in order to extend DEX plasma concentrations. Objective: To assess the bioavailability (BA) of DEX MR OD 30 mg tablet swallowed intact with water or mixed with water and administered via nasogastric (NG) tube or oral syringe compared to administration of DEX MR OD 30 mg on the tongue, allowed to disintegrate, and swallowed without water. Methods: This was a phase 1, randomized, single-dose, 4-period crossover study. Qualified healthy subjects 18-55 years old received a single oral dose of 30 mg DEX MR OD as an intact tablet administered on the tongue, swallowed intact, or mixed with water and administered via oral syringe or NG tube. Each study period was followed by a 5-day washout. Blood samples for determination of plasma pharmacokinetics were collected for 24 hours post-dose in each period. Analyses of variance models were performed, and bioequivalence (BE) between an administration option and DEX MR OD administered on the tongue without water was declared if 90% confidence intervals (CIs) of central value ratios between 2 regimens for maximum plasma concentration (Cmax) and area under the curve (AUC) mean ratios were contained within the BE limits of 0.80-1.25. Safety was assessed via physical examination (PE), clinical laboratory evaluation, vital sign assessment, electrocardiograms (ECG), and adverse event reports (AE). Results: Seventy-seven subjects (mean age 38±9.8 years) were enrolled. The 90% CIs for the BA of DEX MR OD 30 mg administered via oral syringe or NG tube, or swallowed intact, relative to that from administration of DEX MR OD on the tongue without water, for Cmax and AUCs were within the BE range of 0.80-1.25 (TABLE). All 4 regimens were well tolerated. AEs were mild in intensity and were considered not related to study drug. Percentages of subjects experiencing AEs were comparable across the 4 regimens. There were no clinically important findings noted in the PE, safety clinical laboratory, vital sign, or ECG reports. Conclusions: DEX MR OD 30 mg administered as an aqueous mixture via an oral syringe or an NG tube, or as an intact tablet swallowed with water was each BE to the administration of the DEX MR OD 30 mg on the tongue without water. Single oral doses of DEX MR OD tablets were well tolerated in this study. Table. BE Assessment of Administration Routes for DEX MR OD Tablets

(404) Extraction testing of a novel extended-release, abuse-deterrent formulation of morphine, Morphine ARER, in common household solvents

Abusers of prescription opioids commonly extract the active ingredient from non-abuse deterrent, extended-release formulations to bypass the intended slow release characteristics and increase the opioid’s bioavailability for injection, smoking, or oral administration. Abuse deterrent products are designed to increase the hurdles required to extract the active ingredient with the ultimate goal of decreasing the misuse and abuse of these formulations for all routes of administration dependent on extraction. The FDA’s Draft Guidance for Industry, Abuse-Deterrent Opioids – Evaluation and Labeling (January 2013) recommends that laboratory-based in vitro manipulation and extraction studies be performed to evaluate the physical characteristics of a novel product and to guide the downstream pharmacokinetic (PK) and clinical abuse studies. To assess the abuse deterrent properties of an investigational extended-release formulation of morphine, Morphine ARER, in vitro laboratory testing was performed to assess the extractability of morphine. Five intact and five finely crushed tablets were dissolved in 30 mL of household solvents including water, saline solution, vinegar, coke, pH 2, pH 4, pH 6, pH 10, 5% ethanol, 10% ethanol, 20% ethanol, 40% ethanol, and 90oC water. The percent of morphine released was assessed via liquid chromatography. Morphine ARER did not dose dump morphine under any condition or solution. Water was found to be the best solvent for extraction. Interestingly, the amount of morphine released was largely similar between crushed and intact tablets and reduced in increasing concentrations of ethanol. These data clearly indicate that Morphine ARER was highly resistant to extraction and did not result dose dumping either from intact or ground tablets, even at 30 minutes, which is longer than an abuser would be expected to wait. Funding Provided by Inspirion Delivery Technologies LLC.

Investigating the properties of subcritical water extraction with pharmaceutical tablets

The properties of subcritical water extraction (SWE) in the sample preparation of pharmaceutical tablets were investigated. Tablets comprised of microcrystalline cellulose excipients broke apart up to 80 times faster in subcritical water than they did in room temperature water, while those containing starch readily broke apart in either. Tablets containing starch were also observed to gelatinize or “paste” over several SWE conditions, impeding subsequent filtration and analysis. This effect was avoidable, however, since it was demonstrated to disappear with increases in extraction time and temperature or decreases in sample size. Using SWE, two common over-the-counter pharmaceuticals were extracted under optimized conditions from tablets comprised of either microcrystalline cellulose or starch excipients. Analyte recoveries of 95% or more were obtained at 150 °C for vitamin C (ascorbic acid) tablets in as little as 8 min for the extraction of a whole intact tablet, 6 min for two half tablets, and 5 min for a ground tablet. By comparison, this occurred at 250 °C in just 2 min for an intact slice of an acetaminophen tablet. Reproducibility was generally quite good with these trials producing RSD values of less than 2%. The results indicate that SWE can be a potentially viable and efficient method for the sample preparation of whole, sliced, or ground pharmaceutical tablets, and further exploration of this approach is promising.

Evolution of Structure and Properties of Granules Containing Microcrystalline Cellulose and Polyvinylpyrrolidone During High-Shear Wet Granulation

Granulation behavior of microcrystalline cellulose (MCC) in the presence of 2.5% polyvinylpyrrolidone (PVP) was systematically studied. Complex changes in flowability and tabletability of lubricated MCC granules are correlated to changes in intragranular porosity, morphology, surface smoothness, size distribution, and specific surface area (SSA). With 2.5% PVP, the use of 45% granulation water leads to 84% reduction in tablet tensile strength and 76% improvement in powder flow factor. The changes in powder performance are explained by granule densification and surface smoothing. The granulating water level corresponding to the onset of overgranulation, 45%, is significantly lower than the 70% water required for unlubricated MCC granules without PVP. At more than 45% water levels, MCC–PVP granules flow well but cannot be compressed into intact tablets. Such changes in powder performance correspond to the rapid growth into large and dense spheres with smooth surface. Compared with MCC alone, the onset of the phase of fast granule size enlargement occurs at a lower water level when 2.5% PVP is used. Although the use of 2.5% PVP hastens granule nucleation and growth rate, the mechanisms of overgranulation are the same, that is, size enlargement, granule densification, surface smoothing, and particle rounding in both systems.

Ghost pill: knowledge and awareness of this phenomenon among health care professionals

Background: Slow release (SR) drug formulations associated with the passage of intact tablet like object in faeces sometimes known as the “ghost pill” have been in the market for many years. Anecdotal evidence suggests that few health care professionals are aware of this phenomenon. Our study aims were to find out what proportion of health care professionals was aware of the ghost pill phenomena and what drug formulations and specific drugs were associated with it. Methods: A survey was conducted among health care professionals at three hospital sights in the West Midlands, UK. The subjects included doctors, nursing staff, pharmacists, and other allied professionals involved in patient care. Results: A total of 321 health care professionals were included in the final analysis. Very few, 12.8% (41) have heard of the ghost pill phenomenon and a further 14 (4.4%) have come across of a patient who has experienced it. Only 13 (4%) correctly associated the phenomenon with SR drug formulations. Conclusion: Our survey has shown that the ghost pill phenomenon, a normal outcome of a novel way of delivering orally taken SR drugs, is not well-known among health care professionals. Lack of awareness of it has implications to trainers, medical and nonmedical prescribers and nursing staff working with patients who are taking these medications. Lack of awareness among health care staff, may result in relevant information not being shared with patients at the time of prescribing or when patients enquires of it.

Feasibility Study of Diffuse Reflectance and Transmittance near Infrared Spectroscopy for Rapid Analysis of Ascorbic Acid Concentration in Bilayer Tablets Using a High-Speed Polychromator-Type Spectrometer

The feasibility of real-time release testing of bilayer tablets was investigated using near infrared (NIR) spectroscopy. The newly developed polychromator-type NIR spectrometer was used to compare the diffuse reflectance (DR) and transmittance (Tr) NIR spectroscopic techniques. This spectrometer not only performs highly sensitive NIR measurements but also yields the NIR spectra of an intact tablet on a millisecond (ms) timescale; i.e. 500 ms for the DR-NIR measurements and 400 ms for the Tr-NIR measurements. The bilayer tablets were prepared with the first layer comprising 0–10% ascorbic acid (AsA), 20% corn starch, 5% talc, 30% microcrystalline cellulose and 45–35% lactose, and the second layer comprising 20% corn starch, 5% talc, 30% microcrystalline cellulose and 45% lactose; their DR-and Tr-NIR spectra were acquired from both sides of the tablet. With these spectra, the feasibility of DR- and Tr-NIR spectroscopy for the quantitative analysis of AsA in the bilayer tablets was compared. The DR- and Tr-NIR spectra of the bilayer tablets and their second-derivative spectra were studied. The AsA bands were not identified in the DR- and Tr-NIR spectra. However, the AsA bands at 995 nm and 1458 nm were observed in the second-derivative spectra. All the developed regression models predicted the AsA concentration, and regression vectors indicated that the prediction was based on the AsA bands. In addition, the model using the Tr-NIR spectra was able to predict the AsA concentration, even when the bilayer tablet was flipped.

Direct detection and identification of active pharmaceutical ingredients in intact tablets by helium plasma ionization (HePI) mass spectrometry

A simple modification converts an electrospray ion source to an ambient-pressure helium plasma ionization source without the need of additional expensive hardware. Peaks for active ingredients were observed in the spectra recorded from intact pharmaceutical tablets placed in this source. A flow of heated nitrogen was used to thermally desorb analytes to gas phase. The desorption temperatures were sometimes as low as 50°C. For example, negative-ion spectra recorded from an aspirin tablet showed peaks at m/z 137 (salicylate anion) and 179 (acetylsalicylate anion) which were absent in the background spectra. The overall ion intensity increased as the desorption gas temperature was elevated. Within the same acquisition experiment, both positive- and negative-ion signals for acetaminophen were recorded from volatiles emanating from Tylenol tablets by switching the polarity of the capillary back and forth. Moreover, different preparations of acetaminophen tablets could be distinguished by their ion-intensity thermograms.

Quantification, Mechanism, and Mitigation of Active Ingredient Phase Transformation in Tablets

Model tablet formulations containing thiamine hydrochloride [as a nonstoichiometric hydrate (NSH)] and dicalcium phosphate dihydrate (DCPD) were prepared. In intact tablets, the water released by dehydration of DCPD mediated the transition of NSH to thiamine hydrochloride hemihydrate (HH). The use of an X-ray microdiffractometer with an area detector enabled us to rapidly and simultaneously monitor both the phase transformations. The spatial information, gained by monitoring the tablet from the surface to the core (depth profiling), revealed that both DCPD dehydration and HH formation progressed from the surface to the tablet core as a function of storage time. Film coating of the tablets with ethyl cellulose caused a decrease in both the reaction rates. There was a pronounced lag time, but once initiated, the transformations occurred simultaneously throughout the tablet. Thus the difference in the phase transformation behavior between the uncoated and the coated tablets could not have been discerned without the depth profiling. Incorporation of hydrophilic colloidal silica as a formulation component further slowed down the transformations. By acting as a water scavenger it maintained a very "dry" environment in the tablet matrix. Finally, by coating the NSH particles with hydrophobic colloidal silica, the formation of HH was further substantially decelerated. The microdiffractometric technique not only enabled direct analyses of tablets but also provided the critical spatial information. This helped in the selection of excipients with appropriate functionality to prevent the in situ phase transformations.

Phase I Pharmacokinetic and Pharmacodynamic Study of Pazopanib in Children With Soft Tissue Sarcoma and Other Refractory Solid Tumors: A Children's Oncology Group Phase I Consortium Report

Pazopanib, an oral multikinase angiogenesis inhibitor, prolongs progression-free survival in adults with soft tissue sarcoma (STS). A phase I pharmacokinetic and pharmacodynamic study of two formulations of pazopanib was performed in children with STS or other refractory solid tumors. Pazopanib (tablet formulation) was administered once daily in 28-day cycles at four dose levels (275 to 600 mg/m(2)) using the rolling-six design. Dose determination for a powder suspension was initiated at 50% of the maximum-tolerated dose (MTD) for the intact tablet. Ten patients with STS underwent dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) scanning at baseline and 15 ± 2 days after initiation of pazopanib at the tablet MTD. Fifty-three patients were enrolled; 51 were eligible (26 males; median age, 12.9 years; range, 3.8 to 23.9 years). Hematologic and nonhematologic toxicities were generally mild, with dose-limiting lipase, amylase, and ALT elevation, proteinuria, and hypertension. One patient with occult brain metastasis had grade 4 intracranial hemorrhage. The MTD was 450 mg/m(2) for tablet and 160 mg/m(2) for suspension. Steady-state trough concentrations were reached by day 15 and did not seem to be dose dependent. One patient each with hepatoblastoma or desmoplastic small round cell tumor achieved a partial response; eight patients had stable disease for ≥ six cycles, seven of whom had sarcoma. All patients with evaluable DCE-MRI (n = 8) experienced decreases in tumor blood volume and permeability (P < .01). Placental growth factor increased, whereas endoglin and soluble vascular endothelial growth factor receptor-2 decreased (P < .01; n = 41). Pazopanib is well tolerated in children, with evidence of antiangiogenic effect and potential clinical benefit in pediatric sarcoma.