Intra and Extra-granular Disintegrant Properties of Modified Underutilised Red Lima Bean Starch in Paracetamol Tablet Formulation

Abstract Red lima bean (Phaseolus lunatus Linn) Family Fabaceae, has been modified by succinylation and annealing, and used as intra- and extra-granular disintegrants at concentrations of 5 and 10 %w/w in paracetamol tablet formulation in comparison with corn starch BP. The starches were characterised using FT-IR spectroscopy, SEM, proximate analysis, physicochemical and functional properties. FT-IR spectrometry revealed characteristic peaks at 1575.53 and 1713.99 cm-1 for the succinylated starch while the annealed showed no significant difference from the native starch. Modifications did not alter the ovoid shape of the native starch but reduced the particle size. Succinylation improved water absorption capacity, solubility and swelling of lima bean starch but annealing reduced the parameters. Tablets with disintegrants of lima bean starches generally had higher crushing strengths and lower friability than tablets with corn starch. Modifications reduced the disintegration time of the tablets when the starches were incorporated intra-granularly, which suggested particle-particle bond interruption and destruction of hydrogen bonds as mechanism of disintegration. Tablets containing 10 %w/w succinylated red lima bean starch incorporated intra-granularly had the highest disintegration efficiency ratio, DER, indicating a great balance between mechanical and disintegration properties. Modified red lima bean starches incorporated intra-granularly into paracetamol tablets led to faster disintegration and could efficiently substitute corn starch as disintegrant.

Saliva vs. plasma bioequivalence of paracetamol in humans: validation of class I drugs of the salivary excretion classification system.

AIMS: To study saliva and plasma bioequivalence of paracetamol in healthy human volunteers, and to investigate the robustness of using saliva instead of plasma as surrogate for bioequivalence of class I drugs according to the salivary excretion classification system (SECS). METHODS: Saliva and plasma pharmacokinetic parameters were calculated by non compartmental analysis. Analysis of variance, 90% confidence intervals, intra-subject and inter-subject variability values of pharmacokinetic parameters were calculated after logarithmic transformation. Calculations were done using Kinetica program V5. Descriptive and comparative statistics were also calculated by Excel. RESULTS AND DISCUSSION: Paracetamol falls into class I (High permeability/High fraction unbound to plasma proteins) and was subjected to salivary excretion, with correlation coefficient of 0.99 between saliva and plasma concentrations and saliva/plasma concentrations ratios of 1.45-1.50. The 90% confidence limits of areas under curve (AUC(last) and AUC(∞)) showed similar trend and passed the 80-125% acceptance criteria in both saliva and plasma. On the other hand for maximum concentration (C(max)), the 90% confidence limits passed the acceptance criteria in plasma and failed in saliva. Inter and intra subject variability values in saliva were higher than plasma leading to need for higher number of subjects to be used in saliva. Saliva and plasma parameter ratios were not significantly different (P>0.05). CONCLUSIONS: Saliva instead of plasma can be used as surrogate for bioequivalence of class I drugs according to SECS when adequate sample size is used. Future work is planned to demonstrate SECS robustness in drugs that fall into classes II or III.

Crystal structure determination of the elusive paracetamol Form III.

The previously unknown crystal structure of the elusive Form III of paracetamol has been solved using high quality laboratory X-ray powder diffraction (XRPD) data and state-of-the-art crystal structure prediction (CSP).

Efectos de la colestásis sobre la toxicidad hepática del acetaminofen en ratas / The effects of cholestasis on the hepatotoxicity of acetaminophen in rats

Existen evidencias clínicas y experimentales de la toxicidad del acetaminofen en altas dosis. La toxicidad ha sido relacionada con un producto metabólico de la droga, a través del citocromo P-450. Pensando que la colestásis, al interferir con la excreción de productos tóxicos o modificar la actividad del P-450 puede incrementar la toxicidad de ciertos medicamentos y en vista del amplio uso del acetaminofen, planificamos un estudio para evaluar su toxicidad en ratas con obstrucción de vías biliares. Se usaron ratas Sprague Dawley, machos, entre 250 y 400 gr. de peso, distribuidas en grupos de 6 animales cada uno: grupo I, considerado control, al cual se le ligó el colédeco y se le administró solución salina al 0,9 por ciento IP (2 dosis de 0,2 ml/100 gr de peso). El grupo II también con ligadura de colédeco, recibió acetaminofen en solución IP, 400 mg/Kg de peso (2 dosis). Este grupo se distribuyó en dos subgrupos de 6 animales cada uno, los cuales fueron sacrificados a las 48 y a las 120 horas respectivamente. A todos se les determinó Bilirrubina total, bilirrubina directa y bilirrubina indirecta, fosfatasas alcalinas, transaminasas (ALT, AST), hematología completa, peso del higado y estudio histológico de hígado y riñón. En los animales con colestásis más acetaminofen hubo un aumento significativo de las transaminasas con respecto a los controles y una elevada incidencia de necrosis hepática en el estudio histológico de hígado (66 por ciento de los casos contra 20 por ciento del control). El tiempo de experimentaciión (48 y 120 horas), no afectó los resultados. La bilirrubina y el peso del hígado no variaron significativamente. Se concluye que la colestásis reciente potencia la toxicidad del acetaminofen a ½ dosis tóxica de la reportada en la literatura para ratas, aparentemente induciendo la actividad del sistema de oxidación mixta del citocromo P-450