J. G. van der Watt

Kinetic study of the solid-state photolytic degradation of two polymorphic forms of furosemide

Abstract In this paper some aspects influencing the solid-state photolytic degradation of two polymorphic forms of furosemide were investigated. Powder samples of the two polymorphic forms were exposed to prolonged UV irradiation, direct sunlight, in a normal and nitrogen atmosphere. The solid-state photolytic degradation of furosemide followed apparent first-order kinetics as described by a model consisting of nucleation and growth periods with eventual deceleration as it reached a maximum fraction degraded. Kinetic calculations revealed that this bilateral first-order degradation process was best described by a power law dependence (n = 2) of the fraction decomposed (α) on time (t) for the nucleation period and first-order kinetic degradation with an asymptote for the growth and deceleration period (Prout-Tompkins model). Overall, the rate constants during the nucleation period were significantly smaller than the growth period. Form I was photochemically more stable than form II, especially under a nitrogen atmosphere ( t 1 2 50 h ). The photolytic degradation of form II was not influenced by the presence of oxygen ( t 1 2 35 h under normal atmospheric conditions and 38 h in a nitrogen atmosphere). After exposure to sunlight 4-chloro-5-sulphamoylanthranilic acid (CSA) was found in significant concentrations in samples taken from both forms I and II. Photolytic degradation of furosemide form II led to the formation of mainly CSA in the presence of nitrogen and CSA and other unidentified products in the presence of oxygen.

The effect of the particle size of microcrystalline cellulose on tablet properties in mixtures with magnesium stearate

Abstract Magnesium stearate was mixed with different sieved fractions (80–180, 180–250, 250–350 μm) of microcrystalline cellulose (Avicel PH 102). The influence of mixing time on crushing strength and disintegration of tablets compressed from these mixtures were studied. The disintegration time increased and the crushing strength decreased with increasing particle size of the Avicel fractions. When magnesium stearate is mixed with table excipients the size of these materials could have an effect on the deterioration of the tablet properties as a function of mixing time.

Structure-solubility relationship and thermal decomposition of furosemide.

Furosemide, a high ceiling diuretic, decomposes on heating and is very sparingly soluble in water. The aim of this study was to identify the thermal decomposition product(s) of furosemide and to calculate the activation energy needed for this reaction. This was done to gain a better understanding of the unusually low water solubility of this drug. The main thermal decomposition product was identified by nuclear magnetic resonance (NMR), mass spectrometry (MS), and infrared (IR) analysis as 4-chloro-5-sulfamoylanthranilic acid (saluamine), and the activation energy, calculated from thermogravimetric analysis (TGA) measurements, for this reaction was 47.7 (±1.93) kcal/mol. The experimentally measured activation energy was well below the normal 59 ± 4 kcal/mol needed for the cleavage of the C–N bond to form saluamine. This could possibly be explained by the weakening of the C–N bond through the I–effect of the furane ring and the delocalization of the electrons of the aniline nitrogen in the chlorosulfamoyl benzoic acid entity of furosemide. This decomposition of furosemide indicates the breaking of intramolecular bonds before those of intermolecular bonds (separation of individual furosemide molecules). Strong inter- and intramolecular bonds are a probable cause for the poor water solubility of furosemide because, when some of the inter- and intramolecular bonds that form part of the hydrogen bond network disappeared, as in the structurally related decomposition product saluamine, the aqueous solubility increased.

Influence of surfactants and interactive mixing on the cohesiveproperties of a poorly wettable solid

Abstract The effect of different surface active agents and interactive mixing with high density carrier particles on the dispersion of cohesive furosemide particle agglomerates in aqueous mediums were studied. The individual mean volume particle size of the furosemide powder was 2.5 μm when measured with a dry dispersion apparatus. The particle size distribution was unimodal. Suspended in water the particle size distribution consisted of three distinguishable populations. The addition of surface active agents led to a decrease in the mean particle size, fewer populations were observed and the mean size of these populations were smaller. The addition of polyoxyethylene sorbitan monooleate, 0.011 g dm−3, leads to a decrease in the mean volume particle size from 32.31 μm measured in water, to 11.01 μm Depending on the mixing time, 64 min and longer, interactive mixing with high density sodium chloride particles was the most effective at dispersing the furosemide agglomerates but a bimodal particle size distribution was still observed. The mean volume particle size of furosemide particles mixed for 128 min, 7.79 μm was closest to the mean volume particle size measured with the dry dispersion technique.

The interconversion of the polymorphic forms of chloramphenicol palmitate (CAP) as a function of environmental temperature

AbstractWhen polymorph B of chloramphenicol palmitate (CAP) is heated at 82 °C for 1600 minutes it changes completely to the less soluble and less bioavailable polymorph A. When polymorph C, the most soluble polymorph, is grinded for a prolonged period it changes to polymorph A through B. We investigated the effect of the environmental temperature on the interconversion of polymorph C. This was done to determine the effect that heat generated during grinding could have on polymorph C.Samples of polymorph C was kept at 50 and 75 °C respectively. At predetermined intervals samples were withdrawn and differential scanning colorimetric (DSC) curves and Xray powder diffractograms recorded.Both samples changed to polymorph B but only the sample kept at 75 °C changed into A during the time the experiment was run. Therefore temperature control during storage and handling, especially grinding, of polymorph C and B is recommended to prevent conversion to the poorly soluble and less bioavailable polymorph A.

The effect of processing variables on the compression properties of controlled release core-in-cup compressed tablets from a new adjustable punch

Abstract A novel adjustable punch that can be adjusted to produce compressed cup-shape tablets of different depth has been evaluated. The resultant cups have been compressed together with core tablets to produce compression coated tablets that have the ability to release active drug at a zero-order rate. The influence of three independent variables (percentage carnauba wax in the cup tablet, the compressed hardness of the cup tablet, and depth of the cup tablet) on the friability of the cup tablet and splitting of the cup tablet in aqueous dissolution fluid was studied using a 3 3 factorial design. The friability of the cup tablets were influenced by all the factors as well as the second-order interaction effects. The splitting of the cup tablets were only significantly influenced by the depth of the cup tablet and the hardness of the cup tablets. Core-in-cup tablets containing 5% w/w HPMC K4M in ibuprofen as the core, 4 mm final cup depth, 15% carnauba wax in ethylcellulose as the cup, and compressed to a cup hardness of approx. 100 N/m 2 and final core-in-cup hardness of approx. 160 N/m 2 , released ibuprofen at zero-order rate of release for up to 18 h.

The Effect of Processing Variables on the Release of Ibuprofen and Caffeine from Controlled-Release Nonswellable Core-in-Cup Compressed Tablets

An aqueous soluble polymer such as hydroxypropyl methylcellulose (HPMC), which is widely used in oral sustained-release drug delivery systems, swells when it comes into contact with an aqueous environment. In core-in-cup systems the swelling of the HPMC splits open the cup portion of the tablet. This study investigated the use of acacia, tragacanth, polyethylene glycol 6ooo (PEG 6ooo), and hydroxyethylcellulose (HEC) as possible alternatives to the use of HPMC to control the release of cageine (soluble) and ibuprofen (insoluble) from core-in-cup compressed tablets. It also investigated the possibility of producing a core-in-cup system that had the ability to release caffeine and ibuprofen for a maximum time of constant release of 8-12 hr. A preliminary study revealed that acacia was most eflective for the release of caffeiinefrom the core-in-cup compressed tablets, and that PEG 6cux) was most effective for the release of ibuprofen from the core-in-cup compressed tablets. On further investigation it was found that by means of adjusting the hardness of compression and the concentration of polymers used, it was possible to formulate a core-in-cup system that could release drug at a constant rate from the core-in-cup compressed tablets for 8 to 12 hr.

Dissolution Rate A Measurement of the Deaggregation of Furosemide Agglomerates During An Interactive Mixing Process

AbstractAgglomerates of drug particles must be broken down and single particles attached to the carrier to ensure a completely random interactive mixture. Here it was found that the dissolution rates of samples from interactive mixtures compared to suspended furosemide was an indication of the deaggregation of furosemide agglomerates during an interactive mixing process. Deaggregation depended on the forces generated during mixing and was quicker when a high density carrier such as sodium chloride was used.

Zero-Order Release of Theophylline from a Core-in-Cup Tablet in Sequenced Simulated Gastric and Intestinal Fluid

Core-in-cup tablets containing theophylline were evaluated for their dissolution characteristics in sequenced simulated gastric fluid (SGF) followed by simulated intestinalfluid (SIF). Core-in-cup tablets containing 10% w/w, 20% w/w, and 30% w/w acacia as binder were evaluated for their effects on the time course of release of theophylline. This was done to optimize a formula that could release theophylline at a zero-order rate of release for 8-16 hr in simulated gastrointestinal fluids. Theophylline was released and dissolved from the core-in-cup tablets at a rate that is more consistent with a zero-order dissolution rate than a first-order dissolution rate in both SIG and SIF. The dissolution rates of theophylline from the 10%, 20%, and 30% acacia core-in-cup tablets were 0.87 mg/min, 0.53 mg/min, and 0.27 mg/min, respectively in SGF, and 0.61 mg/min, 0.30 mg/min, and 0.20 mg/min, respectively in SIF. The results indicate that a concentration of 32% w/w acacia in the core tablet will release theophylline at a rate of 0.14 mg/min in SGF for 2 hr followed by SIF for 10 hr.

Influence of the cohesive behaviour of small particles on the solid-state photolytic degradation of furosemide

AbstractThe effect of the cohesive behaviour of small particles on the solid-state photochemical degradation of furosemide is reported. Samples of agglomerated and recrystallised separated particles were exposed to direct sunlight for up to 240 hours, and the furosemide content measured with time. The solid-state photolytic degradation of furosemide proceeds from a nucleation period, through a growth period and eventual deceleration of the reaction. The kinetic process was best described by a power law dependence of the fraction degraded on time for the nucleation period and first order kinetics with asymptote, Prout-Tompkins equation, for the growth of the nuclei. The first order rate constants for the degradation of the agglomerated and the separated particles were 1.20 × 10-2 hour-1 and 1.48 × 10-2 hour-1 respectively for the nucleation period and 2.85 × 102 hour-1 and 2.45 × 10-2 hour-1 for the growth period. Although the mean particle size of the particles which made up the agglomerates was significa...