A Statistical Approach to Evaluating the Manufacture of Furosemide Tablets - Pharmaceutical Technology

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A Statistical Approach to Evaluating the Manufacture of Furosemide Tablets
The authors evaluated the manufacturing data of 40-mg tablets of furosemide, a potent diuretic.


Pharmaceutical Technology
Volume 35, Issue 3, pp. 112-121

Materials


Table II: Values of the Anderson–Darling statistics (AD) and p-values performed for powder mixture conformity, uniformity of dosage units, and % released.
Furosemide was supplied by Alcon Biosciences. Crospovidone was provided by ISP. Lactose monohydrate was purchased from Doremus. Talc was supplied by Indukern, and magnesium stearate by Inbra. The authors bought pregelatinized starch from Colorcon and maize starch from Cargill. Purified water was supplied by Prati-Donaduzzi. All the materials were of Brazilian Pharmacopoeia grade, as stated by the suppliers.

Methods


Table III: Estimated variance component for furosemide content in the powder blend.
Manufacturing process of 40-mg furosemide tablets. Three consecutive 380-kg batches of 40-mg furosemide tablets were manufactured by wet granulation. The powders were mixed in a bin blender (VZD-400, Vanguard) for 20 min. at 18 rpm (see Figure 1). Next, powders were sieved through a 0.5-mm sieve and loaded into the high-shear mixer (MIC-P, Comasa, Buenos Aires). The granulation liquid was then sprayed tangentially into the moving powder mixture using a pneumatic atomizer at 1.0 bar atomizing air pressure and a speed of 80 rpm. The powder was mixed for 5 min. before the granulation was started. The spray rate was 40 g/min. The granules passed through a 2.5-mm sieve, dried at 50 ±3 °C in an oven for 24 h, passed through a 1.25-mm screen, and finally lubricated with magnesium stearate. The compression was performed employing a 50-station double rotary tableting machine (2000/50, Lawes, Săo Paulo). The speed was kept constant at 75,000 tablets/h. The Lawes tableting machine was dedicated equipment to produce furosemide tablets only.


Figure 3: Capability analysis of the content (mg) of furosemide in the powder mixture. CL is control level, CP is process capability, Cpk is process-capability index, CPL is process capability relative to lower specification limit, CPU is process capability relative to upper specification limit, LSL is lower specification limit, PPM is parts per million, StDev is standard deviation, and USL is upper specification limit.
Furosemide assay by ultraviolet-visible spectrophotometer. The assays were performed in duplicate according to the Brazilian Pharmacopoeia (11). The ultraviolet-visible (UV-vis) spectrophotometer (800XI, Femto, Săo Paulo), UV λ = 271 nm, was used, and the standard and sample concentrations of furosemide were diluted to 0.6 mg/mL using 0.1 N HCl.


Figure 4: Control charts of individual and moving range (MR) of the individual tablet weights (mg) for the left and right sides of the tableting machine. LCL is lower control limit, LSL is lower specification limit, UCL is upper control limit, USL is upper specification limit, and X is individual value.
Dissolution of furosemide tablets. The dissolution test of furosemide tablets from the different batches (i.e., at the beginning, in the middle, and at the end of the process) was carried out in triplicate using USP Apparatus 2 (paddle method). The dissolution test was performed using 900 mL of pH 5.8 phosphate buffer at 37.0 ±0.5 °C at 50 rpm. Aliquots (5 mL each) were withdrawn at a predetermined time interval of 60 min. The samples were filtered through a 0.45-μm membrane filter. The furosemide assay was performed by spectrophotometer UV-vis (Femto) UV λ = 271 nm. The USP 32 specification for dissolution of furosemide tablets is not less than 80% (Q) of furosemide dissolved in 60 min in 900 mL of pH 5.8 phosphate buffer (12).


Table IV: Tablet weights (mg) for left and right sides of the tableting machine for the three batches.
Sampling plan and statistical analysis. The sampling plan included the collection of 10 g of the powder mixture in 10 specific locations (see Figure 1). For the tablets, a minimum of 200 units on the right and left side of the double rotary tableting machine were collected. The uniformity of dosage units of furosemide was calculated using 30 tablets per batch (i.e., 10 tablets in the beginning, 10 in the middle, and 10 at the end of the tableting process). For the dissolution test, a total of six tablets for each batch—at the beginning, in the middle, and at the end of the process—were analyzed. The statistical analysis of the three consecutive batches was evaluated by using Minitab software, version 15 (Minitab, State College, PA).


Figure 5: Capability analysis of the tablet weights for three batches. Cp is process capability, Cpk is process-capability index, CPL is process capability relative to lower specification limit, CPU is process capability relative to upper specification limit, LSL is lower specification limit, PPM is parts per million, StDev is standard deviation, USL is upper specification limit, and X is individual value.
The process stability was evaluated using individual and moving-range charts as well as standard-deviation charts (I-MR-R/S), considering a subgroup size of 10. The normal distribution was evaluated by the Anderson–Darling test. For non-normal distributions according to the Anderson–Darling test, the Box–Cox family of power transformations was used to obtain an approximate Gaussian distribution (13).


Table V: Tablet weight of furosemide (mg) versus left and right side of the tableting machine.
The process capability indices were calculated when the analyzed parameter was normally distributed or when its distribution was close to the normal distribution (6, 14). The fully nested analysis of variance (ANOVA) was performed to estimate variance components for each response variable (i.e., mixture content, tablet weight, dosage-unit uniformity, and dissolution). All factors were assumed to be random. The mean comparison between the tablet weights from the two sides of the tableting machine was performed using one-way ANOVA.


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