Influence of Superdisintegrants on the Rate of Drug Dissolution from Oral Solid Dosage Forms
The authors examine common superdisintegrants (i.e., crospovidone Type A, crospovidone Type B, croscarmellose sodium, and sodium starch glycolate) with a set of poorly soluble drug actives and evaluate in vitro drug dissolution.
Materials. Table I lists the 13 poorly soluble active ingredients tested. Their aqueous solubilities were 2–2300 µg/mL. The superdisintegrants
studied were crospovidone Type A (Polyplasdone XL, International Specialty Products, ISP, Wayne, NJ), crospovidone Type B
(Polyplasdone XL-10, ISP), croscarmellose sodium (Ac-Di-Sol, FMC Biopolymer, Philadelphia, PA), and sodium starch glycolate
(Glycolys, Roquette, Tokyo). As outlined in the European Pharmacopoeia, crospovidone is available in different particle sizes. Crospovidone Type B has a smaller average particle size than crospovidone
Tablet preparation. Tablets were prepared at the highest market dose using a direct compression (DC) or wet granulation (WG) process as considered
appropriate through a review of the ingredients listed in the Physician's Desk Reference (PDR) and patent literature.
For tablets prepared by direct compression, required ingredient quantities were weighed and blended to form a homogeneous
powder mix. The blends were then compressed using appropriate tooling on a 16-station, instrumented, rotary compression machine
(CMD4, Cadmach, Ahmdedabad, Gujarat, India). Advanced Instrumentation Monitor (AIM) software, (Metropolitan Computing Corporation,
East Hanover, NJ) was used with the tablet press to determine the compression force required to yield tablets of approximately
equal hardness for the various drugs used in the study. Formulations used to prepare atorvastatin and loratadine tablets by
direct compression are shown as examples in Tables II and III, respectively.
For tablets prepared by wet granulation, weighed amounts of drug, diluent, and binder were premixed for 60 s in a granulator
bowl (4M8, Pro-C-Ept, Zelzate, Belgium) at an impeller speed ranging from 1000 to 1200 rpm. Water was added at a predetermined
rate, and after 120 s, the chopper was started (2300–2500 rpm). Granulation proceeded for 10 min. The impeller torque and
the product temperature were monitored to determine the end point of granulation. The granules were sieved through specified
mesh and dried in an oven at 60 °C, to a final moisture content of 1.5–2% w/w, measured using a moisture balance (MA45, Sartorius,
Goettingen, Germany). The required quantities of remaining ingredients were weighed and blended with the granules to form
a homogeneous powder mix. The blends were then compressed as previously described. Formulations used to prepare efavirenz
and ezetimibe tablets by wet granulation are shown as examples in Tables IV and V, respectively.
Tablet evaluation .Tablet strength. The respective breaking forces of the prepared tablets were determined 24 h after compression using a hardness tester (TBH
310 MD, ERWEKA, Heusenstamm, Germany). Ten tablets from each batch prepared were tested for tablet breaking force, and the
mean and standard deviation were calculated.
Figure 1 (All figures are courtesy of the authors)
Disintegration time. Respective disintegration times of the prepared tablets were measured in 900 mL of purified water with disks at 37 °C using
a TAR series tester (ERWEKA). Disintegration times of six individual tablets were recorded.
In vitro dissolution.
The dissolution studies of the prepared tablets were carried out using US Pharmacopeia (USP) Apparatus 2 (Vankel VK, Palo
Alto, CA). Dissolution profiling was performed with the medium recommended by USP or the US Food and Drug Administration for
the respective drug. Dissolution profiling was also carried out in a medium developed in house and derived from the recommended
media, capable of discriminating between the formulations. A peristaltic pump was coupled to a UV–visible spectrophotometer
(Carry 50, Palo Alto, CA) to provide a continuous flow of the drug solution through a 1-cm cuvette. Samples were programmed
to be analyzed at 5, 10, 15, 30, 45, and 60 min at the λ max of the respective drugs. The time required to achieve 80% drug
release (t80) was considered for comparing dissolution results. The t80 was determined by fitting the dissolution data to a four-parametric logistic model using the Marquardt–Levenberg algorithm
(Sigmaplot 9.0, SPSS, Chicago).
In this equation, y represents the cumulative percent of drug released, x is the time in minutes, "min" is the baseline of percent drug released at 0 min, "max" is the plateau of percent drug released
at 60 min, and "hillslope" is the slope of the curve at transition center EC50.