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PubMed1998

The capsule and S-layer: two independent and yet compatible macromolecular structures in Bacillus anthracis.

Bacillus anthracis, the etiological agent of anthrax, is a gram-positive spore-forming bacterium. Fully virulent bacilli are toxinogenic and capsulated. Two abundant surface proteins, including the major antigen, are components of the B. anthracis surface layer (S-layer). The B. anthracis paracrystalline S-layer has previously only been found in noncapsulated vegetative cells. Here we report that the S-layer proteins are also synthesized under conditions where the poly-gamma-D-glutamic acid capsule is present. Structural and immunological analyses show that the capsule is exterior to and completely covers the S-layer proteins. Nevertheless, analysis of single and double S-layer protein mutants shows that the presence of these proteins is not required for normal capsulation of the bacilli. Similarly, the S-layer proteins assemble as a two-dimensional crystal, even in the presence of the capsule. Thus, both structures are compatible, and yet neither is required for the correct formation of the other.

Animals↗
PubMed2002

Impact of phosphorylation of specific residues in the tyrosine autokinase, Wzc, on its activity in assembly of group 1 capsules in Escherichia coli.

Wzc(CPS) is a tyrosine autokinase essential for the assembly of a high-molecular-weight (HMW) group 1 capsular polysaccharide (CPS) in Escherichia coli. Homologues of Wzc participate in the formation of CPS and exopolysaccharides in a variety of gram-positive and gram-negative bacteria. Phosphorylation of tyrosine residues in the Wzc(CPS) C terminus is essential for HMW CPS assembly. Overexpression of Wzb(CPS) (phosphatase) in a wild-type background caused a 3.7-fold decrease in the amount of cell-associated K30 CPS produced, confirming the importance of Wzc(CPS) phosphorylation for capsule assembly. In this study, the tyrosine-rich region was dissected in an attempt to identify residues critical for Wzc(CPS) phosphorylation and/or capsule expression. Site-directed mutagenesis demonstrated that no single tyrosine residue in this region is sufficient for detectable phosphorylation of Wzc(CPS) in vivo or for HMW CPS expression. Furthermore, no single tyrosine residue is essential for phosphorylation or capsule assembly, since removal of any one tyrosine residue has no detectable effect. Altering combinations of tyrosine residues (from two to five) led to Wzc(CPS) derivatives that were still competent for phosphorylation but that could not support assembly of HMW CPS, showing that phosphorylation of Wzc per se is not an accurate measure of its ability to function in capsule assembly. One interpretation of these data is that the overall level of phosphorylation in this region, rather than the precise combination of residues accessible to phosphorylation, is important for the activity of Wzc(CPS). Tyrosine 569, a residue shown to modulate the in vitro phosphorylation of Wzc(CA) from E. coli K-12, was also mutated. The derivative with this mutation still functioned in capsule assembly. Quantitation of K30(CPS) from this mutant revealed no difference in the amount of polymer produced. Finally, dithiobis(succinimidylpropionate) cross-linking was used to confirm that Wzc(CPS) forms complexes in vivo, independent of the phosphorylation state of the protein.

Bacterial Capsules↗
PubMed2003

A novel outer membrane protein, Wzi, is involved in surface assembly of the Escherichia coli K30 group 1 capsule.

Escherichia coli group 1 K antigens form a tightly associated capsule structure on the cell surface. Although the general features of the early steps in capsular polysaccharide biosynthesis have been described, little is known about the later stages that culminate in assembly of a capsular structure on the cell surface. Group 1 capsule biosynthesis gene clusters (cps) in E. coli and Klebsiella pneumoniae include a conserved open reading frame, wzi. The wzi gene is the first of a block of four conserved genes (wzi-wza-wzb-wzc) found in all group 1 K-antigen serotypes. Unlike wza, wzb, and wzc homologs that are found in gene clusters responsible for production of exopolysaccharides (i.e., predominantly cell-free polymer) in a range of bacteria, wzi is found only in systems that assemble capsular polysaccharides. The predicted Wzi protein shows no similarity to any other known proteins in the databases, but computer analysis of Wzi predicted a cleavable signal sequence. Wzi was expressed with a C-terminal hexahistidine tag, purified, and used for the production of specific antibodies that facilitated localization of Wzi to the outer membrane. Circular dichroism spectroscopy indicates that Wzi consists primarily of a beta-barrel structure, and dynamic light scattering studies established that the protein behaves as a monomer in solution. A nonpolar wzi chromosomal mutant retained a mucoid phenotype and remained sensitive to lysis by a K30-specific bacteriophage. However, the mutant showed a significant reduction in cell-bound polymer, with a corresponding increase in cell-free material. Furthermore, examination of the mutant by electron microscopy showed that it lacked a coherent capsule structure. It is proposed that the Wzi protein plays a late role in capsule assembly, perhaps in the process that links high-molecular-weight capsule to the cell surface.

Bacterial Capsules↗
PubMed2004

atxA controls Bacillus anthracis capsule synthesis via acpA and a newly discovered regulator, acpB.

Two regulatory genes, acpA and atxA, have been reported to control expression of the Bacillus anthracis capsule biosynthesis operon capBCAD. The atxA gene is located on the virulence plasmid pXO1, while pXO2 carries acpA and the cap genes. acpA has been viewed as the major regulator of the cap operon because it is essential for capsule gene expression in a pXO1(-) pXO2(+) strain. atxA is essential for toxin gene transcription but has also been implicated in control of the cap genes. The molecular functions of the regulatory proteins are unknown. We examined cap gene expression in a genetically complete pXO1(+) pXO2(+) strain. Our results indicate that another pXO2 gene, acpB (previously called pXO2-53; accession no. NC002146.1:49418-50866), has a role in cap expression. The predicted amino acid sequence of AcpB is 62% similar to that of AcpA and 50% similar to that of AtxA. Assessment of cap gene transcription revealed that cap expression was not affected in a pXO1(+) pXO2(+) acpB-null mutant and was slightly reduced in an isogenic acpA mutant. However, cap gene expression was abolished in an acpA acpB double mutant. Microscopic examination of capsule synthesis by the mutants corroborated these findings. acpA and acpB expression is controlled by atxA; capsule synthesis and transcription of acpA and acpB were markedly reduced in an atxA mutant. The data suggest that, in a strain containing both virulence plasmids, atxA is the major regulator of capsule synthesis and controls capBCAD expression indirectly, via positive regulation of acpA and acpB.

Amino Acid Sequence↗
PubMed2005

Identification of an Escherichia coli operon required for formation of the O-antigen capsule.

Escherichia coli produces polysaccharide capsules that, based on their mechanisms of synthesis and assembly, have been classified into four groups. The group 4 capsule (G4C) polysaccharide is frequently identical to that of the cognate lipopolysaccharide O side chain and has, therefore, also been termed the O-antigen capsule. The genes involved in the assembly of the group 1, 2, and 3 capsules have been described, but those required for G4C assembly remained obscure. We found that enteropathogenic E. coli (EPEC) produces G4C, and we identified an operon containing seven genes, ymcD, ymcC, ymcB, ymcA, yccZ, etp, and etk, which are required for formation of the capsule. The encoded proteins appear to constitute a polysaccharide secretion system. The G4C operon is absent from the genomes of enteroaggregative E. coli and uropathogenic E. coli. E. coli K-12 contains the G4C operon but does not express it, because of the presence of IS1 at its promoter region. In contrast, EPEC, enterohemorrhagic E. coli, and Shigella species possess an intact G4C operon.

Bacterial Capsules↗
PubMed1994

Impaired oesophageal transit of capsule versus tablet formulations in the elderly.

Drug induced oesophageal injury is an important and preventable cause of iatrogenic injury. In most cases the injury is considered to be due to mucosal contact from formulations lodged in the oesophagus. A scintigraphic study was performed comparing the oesophageal transit of enteric coated tablets with similar sized and shaped gelatin capsules, using a population of elderly healthy volunteers similar in age (50-79 years) to the population most likely to be receiving regular treatment. Twenty three volunteers injected the radiolabelled tablet or capsule with 50 ml of water while sitting on two separate occasions according to a randomisation schedule. Oesophageal transit was assessed by gamma scintigraphy. Gastric residence was also assessed in 11 of 23 subjects. While the tablet was readily cleared from the oesophagus, mean transit time 4.3 seconds (range 1.0-14.0), the capsule often showed a comparatively prolonged holdup, mean transit time 20.9 seconds (range 1.5-174.5). Ten of 11 tablets emptied from the stomach intact, while all 11 capsules broke up in the stomach. Gelatin capsules showed a clear tendency to remain within the oesophagus of healthy elderly volunteers, while similar sized enteric coated tablets did not. These studies show the importance of assessing oesophageal transit when designing the formulation of drugs with a potential for oesophageal injury.

Administration, Oral↗
PubMed1997

Itraconazole solution: higher serum drug concentrations and better clinical response rates than the capsule formulation in acquired immunodeficiency syndrome patients with candidosis.

AIMS: To compare the serum concentrations of itraconazole and hydroxyitraconazole after treatment with itraconazole cyclodextrin solution and itraconazole capsules in human immunodeficiency virus (HIV) positive patients with oral candidosis. METHODS: The pharmacokinetics of itraconazole and its active metabolite hydroxy-itraconazole were assessed on days 1 and 7 of therapy in acquired immunodeficiency syndrome (AIDS) patients with oral candidosis taking either itraconazole solution or capsules and the serum concentrations (measured by high performance liquid chromatography) correlated with the clinical response to therapy. In addition, the in vitro susceptibility of Candida spp isolates taken from patients at the start of the therapy was assessed. RESULTS: Nine of 16 patients treated with itraconazole capsules and eight of 15 treated with the solution responded to treatment. Three of the non-responders in each treatment group were infected with isolates resistant to itraconazole in vitro. Although with both preparations there was considerable inter-patient variability in the maximum recorded serum concentrations of itraconazole, they were significantly lower on day 1 and day 7 in those receiving capsules compared with those taking the solution. Patients unresponsive to therapy, but infected with susceptible isolates, had significantly lower concentrations of itraconazole and hydroxyitraconazole levels on days 1 and 7 than patients responding to treatment. However, patients infected with itraconazole resistant isolates (tested in vitro) failed to respond to treatment despite achieving similar serum concentrations of itraconazole and hydroxy-itraconazole to the responsive patients. For patients with in vitro susceptible isolates a serum itraconazole concentration of < 1000 ng/ml on day 7 was predictive of therapeutic failure (specificity 71%, sensitivity 100%). CONCLUSIONS: Itraconazole cyclodextrin solution achieves higher serum itraconazole and hydroxy-itraconazole concentrations than the capsule formulation in AIDS patients, and this is associated with improved efficacy.

AIDS-Related Opportunistic Infections↗
PubMedDate not supplied

Pharmacokinetics and pharmacodynamics during treatment with the omeprazole 20 mg enteric-coated tablet and 20 mg capsule in asymptomatic duodenal ulcer patients.

This study compared the 24 h intragastric pH profile and bioavailability at repeated dosing conditions of the omeprazole 20 mg enteric-coated tablet versus the 20 mg capsule. Forty duodenal ulcer patients in asymptomatic remission completed this randomized open two-way crossover study. Omeprazole 20 mg tablets or capsules were administered for seven days in each period. A 24 h pH recording was performed before the start of treatment and on day 7 of each treatment period. Plasma concentrations of omeprazole were determined 24 h after the dose. The treatment periods were separated by two to four weeks. The difference in percentage of time with pH of at least 3 was less than 16% in favour of the tablet (not significant). The estimated mean area under the plasma concentration-time curve as well as the maximum plasma concentration (Cmax) for omeprazole were 18% and 41% higher, respectively, for the tablet versus the capsule, with the latter percentage being statistically significant. The time to reach Cmax (tmax) with the tablet was, on average, about 0.5 h longer than to reach the tmax of the capsule. This study indicates that the enteric-coated tablet formulation of omeprazole is biodynamically equivalent to the capsule regarding their effects on intragastric pH during repeated dosing.

Adult↗
PubMed2005

Comparative study of antibiotic-containing polymethylmetacrylate capsules and beads.

BACKGROUND: This study aimed at making local antibiotic therapy wider in cases of chronic suppurations by administering antibiotics which previously could not be given in this way through the conventional polymethylmetacrylate (PMMA) carrier techniques. Capsules from this material were produced with a pressing machine designed and laid out by us. The characteristics of antibiotic penetration from this novel carrier were compared to those of PMMA beads. METHODS: The time-dependent outflow of amikacin, clindamycin, pefloxacin, piperacillin + tazobactam, amoxicillin + clavulanic acid and cefotaxime was examined from the capsules and the beads with standard microbiological techniques using the Micrococcus luteus ATCC9341 test strain. The diameter of the inhibitory zones was measured after 24 h incubation at 37 degrees C and converted to mug/ml antibiotic concentrations. RESULTS AND CONCLUSIONS: Our results revealed that all antibiotics showed longer-lasting and higher concentration outflow from the PMMA capsules than from the beads. Therefore, these capsules can provide a more promising new opportunity for specific local antimicrobial treatment in cases of chronic suppurative bone and soft tissue injuries. In these cases the polymerization has already been completed and the heat does not influence the structure of the antibiotics; therefore, it can be inserted into the capsules in powder or solution form.

Amikacin↗
PubMed1993

Pharmacoeconomic comparison of cyclosporine oral solution and capsules after kidney transplantation.

We studied 20 kidney transplant recipients who had received Sandimmune cyclosporine A (CSA) capsules for an average of 7.9 months at a mean dose of 312 mg/day. They were switched to CSA liquid in the same dosage for an average of 15.5 months. There was no significant difference between the means for the monthly values of either serum creatinine or whole blood CSA when the periods on capsules and liquid were compared. Fourteen bottles from 4 batches with volume stated as 50 ml CSA actually contained an average of 53.7 ml. Comparison of the amount of capsules and liquid CSA prescribed and the amount dispensed by the pharmacy showed that the amount neglected (prescribed > dispensed) was similar for patients on liquid and capsules. Wastage (prescribed < dispensed) was about 5% greater when on liquid, and as our cost for liquid was 18% less than for capsules, we saved about 13% by use of the liquid.

Administration, Oral↗
PubMed1989

Theophylline serum levels in children with bronchial asthma after administration of slow release theophylline as open or closed capsules.

Theophylline serum levels were studied after oral administration of slow release theophylline (Talofilina) in children with bronchial asthma. The children received the drug as closed capsules or as granules, obtained by opening the capsules, for 1 week in each form. The mean dose used was 8.6 mg/kg every 12 h. The theophylline blood levels at 4, 8 and 12 h after drug ingestion were significantly lower when granules from open capsules were used. Our recommended dose of Talofilina for Brazilian children is 16 mg/kg/day, if administered as closed capsules, every 12 h. On open capsule administration every 12 h, the total daily recommended dose is 20 mg/kg/day.

Asthma↗
PubMed1996

Imaging of the spatial density distribution on the capsule of the lens with Scheimpflug photography.

The density characteristics of the anterior and posterior surfaces of the lens, although of primary importance for its optical quality, are difficult to determine. Scheimpflug photography, however, allows distinct density measurements from the optical axis towards the periphery with the only limitation of a sufficient mydriasis, so that a 3-dimensional scatter profile of both capsular surfaces can be calculated via multilinear densitometric evaluation of a sufficient number of meridians. On this methodical basis, we analysed Scheimpflug images recorded with the Topcon SL-45 on Kodak T-Max 400 film from 25 patients in an age range between 19 and 63 years. Images from the 0 degree + 45 degree meridians were scanned with multilinear microdensitometry and the data computed to get a density profile. In general, most scattering profiles show a marked interindividual variability. Nevertheless, a general trend can be established between the periphery and the center of the anterior and posterior capsules: (a) the anterior capsule generally has a higher density than the posterior; (b) in most cases, the center of the posterior capsule has a higher density than the periphery; (c) the anterior capsule has a more uniform spatial density distribution in all cases. From the cases evaluated, it can be concluded that the density of the peripheral posterior capsule is more importantly influenced by shading effects of the iris, so that geometrical correction is needed.

Adult↗
PubMed2005

Absence of SPARC in murine lens epithelium leads to increased deposition of laminin-1 in lens capsule.

PURPOSE: To investigate the role of SPARC in the regulation of the expression and deposition of extracellular matrix (ECM) proteins in the lens capsule. METHODS: Wild-type (SP+/+) and SPARC-null (SP-/-) mice of embryonic day (E)14 to 3 months of age were examined. Transcript levels of lens basement membrane (BM) components were analyzed by semiquantitative RT-PCR with mRNA from lens epithelia. Expression of ECM proteins in lens capsule and lens epithelium was analyzed by immunohistochemistry and Western blot analysis. Cell attachment was assessed by lens epithelial explant culture. Coimmunoprecipitation was performed to identify intracellular protein interactions. RESULTS: From postnatal day 5 to 3 months of age, SPARC-null lens capsules exhibited higher levels of laminin-1 deposition relative to their wild-type counterparts, as revealed by immunohistochemistry and immunoblot analysis. An uneven and aggregated distribution of laminin-1 protein was apparent in the anterior region of SPARC-null lens capsules. SPARC and laminin-1 were expressed abundantly in the endoplasmic reticulum (ER) of lens epithelial cells. Coimmunoprecipitation identified that SPARC associates with laminin-1 before laminin secretion. Furthermore, increased laminin-1 in lens capsule promoted the attachment of lens epithelial explants in culture. CONCLUSIONS: SPARC affects the secretion and deposition of laminin-1 protein in lens epithelial cells. Because abnormal deposition of laminin-1 in the lens BM could influence lens epithelial cell adhesion and fiber cell differentiation, the authors propose that SPARC is important to lens homeostasis through its regulation of lens BM matrix organization.

Animals↗
PubMed1992

The K1 capsule is the critical determinant in the development of Escherichia coli meningitis in the rat.

Although Escherichia coli strains possessing the K1 capsule are predominant among isolates from neonatal E. coli meningitis and most of these K1 isolates are associated with a limited number of 0 lipopolysaccharide (LPS) types, the basis of this association of K1 and certain 0 antigens with neonatal E. coli meningitis is not clear. The present study examined in experimental E. coli bacteremia and meningitis in newborn and adult rats whether or not the K1 capsule and/or O-LPS antigen are critical determinants in the development of meningitis. Rats received subcutaneously at K1 E. coli strain (018+K1+) or mutants lacking either the K1 capsule (018+K1-) or 0 side-chain (018-K1+). 12-24 h later, blood and cerebrospinal fluid (CSF) specimens were obtained for quantitative cultures. The isolation of E. coli from CSF was observed in both newborn and adult rats infected with K1+ strains regardless of LPS phenotype (018+ or 18-) who also developed a high degree of bacteremia (e.g., greater than 10(4) CFU/ml of blood). In contrast, none of the newborn and adult rats infected with 018+K1- and developing bacteremia of greater than 10(4) were found to have positive CSF cultures. These findings indicate that the presence of the K1 capsule and a high degree of bacteremia are key determinants in the development of E. coli meningitis, suggesting that there may be specific binding sites present in the brain which have an affinity for the K1 capsule and thus may be responsible for the entry of K1-encapsulated E. coli into the meninges.

Animals↗
PubMed1983

Plasma levels of disopyramide after administration of conventional capsules and sustained-release tablets.

A study was carried out in 33 patients with myocardial infarction and complicating arrhythmias to compare plasma levels of disopyramide attained after administration of conventional capsules or sustained-release tablets. On Day 1, 29 patients started treatment wtih 600 mg disopyramide in 3 divided doses of conventional capsules. In 18, disopyramide plasma concentrations of 3 mg/l or more were achieved within 300 minutes after the first dose. On the second day, patients were allocated at random to receive treatment double-blind for 11 days with 500 mg disopyramide daily given either as conventional capsules (17 patients) or as sustained-release tablets (16 patients). Plasma concentrations were measured just before and 3 hours after the morning dose. Mean maximum and minimum concentrations in the conventional capsule group were 4.4 mg/l and 2.8 mg/l, respectively, compared to 4.3 mg/l and 3.0 mg/l, respectively, in the sustained-release tablet group. For the next 30 days all patients continued treatment with sustained-release tablets. Mean disopyramide plasma concentration measured 15 to 18 hours after the last dose was 2.8 mg/l. Myocardial function was estimated during and 1 week after discontinuing disopyramide treatment. The mean fractional fibre shortening (echocardiography) during treatment was 23% less than that 1 week after discontinuation. The mean PEP/LVET (systolic time interval recording) was 7% higher during treatment compared with 1 week after discontinuation. In 4 cases, mean ejection fraction, measured by scintigraphic methods, during treatment was 10% less than 1 week after discontinuation. Anti-arrhythmic effect was investigated by continuous monitoring in the first 12 days and by Holter monitoring during the 30-day ambulant period and 1 week after discontinuing disopyramide. A significant reappearance of warning arrhythmias could be detected after discontinuing disopyramide sustained-release tablets. No anti-arrhythmic effect was detected in 4 patients. Six patients had to be withdrawn because of side-effects. It is concluded that disopyramide sustained-release tablets 500 mg per day in 2 divided doses gives therapeutic plasma concentrations of 3 mg/l comparable with conventional capsules. A myocardial depressive effect is noted of about 10%.

Adult↗
PubMed2002

Alterations in the lens capsule contribute to cataractogenesis in SPARC-null mice.

The lens capsule, which is also called the lens basement membrane, is a specialized extracellular matrix produced anteriorly by the lens epithelium and posteriorly by newly differentiated fiber cells. SPARC (secreted protein, acidic and rich in cysteine) is a matricellular glycoprotein that regulates cell-cell and cell-matrix interactions, cellular proliferation and differentiation, and the expression of genes encoding extracellular matrix components. SPARC-null mice exhibit lens opacity 1 month after birth and mature cataract and capsular rupture at 5-7 months. In this study, we report disruption of the structural integrity of the lens capsule in mice lacking SPARC. The major structural protein of basement membrane, collagen type IV, in the lens capsule was substantially altered in the absence of SPARC. The lens cells immediately beneath the capsule showed aberrant morphology, with numerous protrusions into the lens basement membrane. SPARC-null lenses at 1 month of age exhibited an increased penetration of dye or radioactive tracer through the capsule, as well as a higher content of water than their wild-type counterparts. Moreover, SPARC-null fibers exhibited swelling as early as 1 month of age; by 3 months, all the fiber cells appeared swollen to a marked degree. By contrast, the absence of SPARC had no apparent morphological effect on the early stages of lens formation, cell proliferation or fiber cell differentiation. Degradation of crystallins and MIP 26, or changes in the levels of these proteins, were not detected. These results underscore the importance of the capsular extracellular matrix in the maintenance of lens transparency and indicate that SPARC participates in the synthesis, assembly and/or stabilization of the lens basement membrane.

Animals↗
PubMed1982

The bioavailability of flufenamic acid from aluminum flufenamate tablet and flufenamic acid capsule, and the influence of food and aluminum hydroxide gel.

The bioavailabilities of flufenamic acid (I) from a commercial aluminum flufenamate (II) tablet and I capsule were estimated by measuring urinary excretion of I and its metabolites fluorometrically. The dissolution rates of I from both dosage forms were also determined. The effects of concomitant intake of food or antacid on the bioavailabilities from the II tablet and the I capsule were investigated. The extent on I bioavailability from the II tablet was less than 30% of that from the I capsule. Dissolution tests suggested that the low bioavailability of I from II tablet resulted from the extremely slow release of I from the II complex. Intake of a standard meal retarded I absorption from I capsule, but did not affect that from the II tablet. Ingestion of dried aluminum hydroxide gel granules had little effect on I bioavailability from the I capsule.

Adult↗
PubMed2002

Mass variation tests for coating tablets and hard capsules: rational application of mass variation tests.

The mass variation test is a simplified alternative test version of the content uniformity test. In the case of coating tablets and capsules, the mass variation test is principally applied to test the inner cores or fillings containing the active ingredient. However, some exceptions exist in pharmacopoeias. The effects of tablet coating and capsule shell on the results of the mass variation test were studied. The mass variation of outer crusts (coatings, capsule shells) and inner cores (core tablets, fillings) was measured separately in several products. The effects of coating on weight variability were very large for sugar-coated tablets. Relative standard deviation (RSD) of the formulation weight (RSD(W)) of sugar-coated tablets (2.73%) was larger than that of plain tablets (0.77%). The cause of the large RSD(W) is the large variation the weight of sugar-coating accounting for 44% of formulation weight. In the case of film-coated tablets, the effect of coating weight on the mass variation test was very small because the rate of coating in comparison to the whole weight was small. In the case of hard capsules, the usage of whole formulation weight resulted in underestimation of variations of filling weight. The differences between dosage forms in the applicability of the mass variation test are caused by differing weight proportions and variability of the outer coatings or shells. To avoid the underestimation of mass variation for hard capsules, a corrected acceptance value is useful. For all the dosage units, the mass variation test can principally be applied to determine which mass is expected to be proportional to the content of the active ingredient. However, some modification of acceptance values enables application of the mass variation tests to inapplicable cases, such as when the RSD of drug concentration (RSD(C)) is larger than 2%.

Algorithms↗