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1.  Disintegration of Highly Soluble Immediate Release Tablets: A Surrogate for Dissolution 
AAPS PharmSciTech  2009;10(2):495-499.
The purpose of the work was to investigate correlation between disintegration and dissolution for immediate release tablets containing a high solubility drug and to identify formulations where disintegration test, instead of the dissolution test, may be used as the acceptance criteria based on International Conference on Harmonization Q6A guidelines. A statistical design of experiments was used to study the effect of filler, binder, disintegrating agent, and tablet hardness on the disintegration and dissolution of verapamil hydrochloride tablets. All formulation variables, i.e., filler, binder, and disintegrating agent, were found to influence tablet dissolution and disintegration, with the filler and disintegrating agent exerting the most significant influence. Slower dissolution was observed with increasing disintegration time when either the filler or the disintegrating agent was kept constant. However, no direct corelationship was observed between the disintegration and dissolution across all formulations due to the interactions between different formulation components. Although all tablets containing sodium carboxymethyl cellulose as the disintegrating agent, disintegrated in less than 3 min, half of them failed to meet the US Pharmacopeia 30 dissolution criteria for the verapamil hydrochloride tablets highlighting the dependence of dissolution process on the formulation components other than the disintegrating agent. The results identified only one formulation as suitable for using the disintegration test, instead of the dissolution test, as drug product acceptance criteria and highlight the need for systematic studies before using the disintegration test, instead of the dissolution test as the drug acceptance criteria.
doi:10.1208/s12249-009-9227-0
PMCID: PMC2690790  PMID: 19387843
disintegration test; dissolution test; ICH Q6A; specification
2.  Dissolution Testing of Sublingual Tablets: A Novel In Vitro Method 
AAPS PharmSciTech  2011;12(2):544-552.
In the sublingual (SL) cavity, compared with the gastrointestinal tract, tablets are subjected to minimal physiological agitation, and a limited volume of saliva is available to facilitate disintegration and dissolution. None of the official compendial dissolution apparatuses and methods simulate these SL conditions. In this study, a custom-made dissolution apparatus was constructed, and a novel in vitro method that simulates SL conditions was evaluated. Several epinephrine 40 mg SL tablet formulations under development and two commercial SL tablets, isosorbide dinitrate 5 mg and nitroglycerin 0.6 mg, were studied. The dissolution medium was 2 mL of distilled water at 25°C. Dissolution was measured at 60 and 120 s. The novel in vitro method was validated for accuracy, reproducibility, and discrimination capability, and was compared with the official US Pharmacopeia (USP) dissolution method using apparatus 2 (Paddle). The data obtained following the novel in vitro method were accurate and reproducible. This method was capable of detecting minor changes in SL formulations that could not be detected using other in vitro tests. Results from the official USP dissolution method and our novel in vitro method were significantly different (p < 0.05). Results reflecting the dissolution of rapidly disintegrating tablets using simulated SL conditions were obtained using the novel in vitro dissolution method.
doi:10.1208/s12249-011-9615-0
PMCID: PMC3134647  PMID: 21523516
custom-made dissolution apparatus; development and validation; dissolution testing; novel in vitro dissolution method; sublingual tablets
3.  Fast-disintegrating sublingual tablets: Effect of epinephrine load on tablet characteristics 
AAPS PharmSciTech  2006;7(2):E72-E78.
The aim of this study was to evaluate the effect of increasing epinephrine load on the characteristics of fast-disintegrating sublingual tablets for the potential emergency treatment of anaphylaxis. Four tablet formulations, A, B, C, and D, containing 0%, 6%, 12%, and 24% of epinephrine bitartrate, respectively, and microcrystalline cellulose:low-substituted hydroxypropyl cellulose (9∶1), were prepared by direct compression, at a range of compression forces. Tablet weight variation, content uniformity, hardness, disintegration time, wetting time, and friability were measured for each formulation at each compression force. All 4 tablet formulations at each compression force were within the United States Pharmacopeia (USP) limits for weight variation and content uniformity. A linear increase in compression force resulted in an exponential increase in hardness for all formulations, a linear increase in disintegration and wetting times of A, and an exponential increase in disintegration and wetting times of B, C, and D. At a mean±SD hardness of ≥2.3±0.2 kg, all tablet formulations passed the USP friability test. At a mean±SD hardness of ≤3.1±0.2 kg, all tablet formulations resulted in disintegration and wetting times of <10 seconds and <30 seconds, respectively. Tablets with drug loads from 0% to 24% epinephrine can be formulated with hardness, disintegration times, and wetting times suitable for sublingual administration.
doi:10.1208/pt070241
PMCID: PMC2750292  PMID: 16796358
sublingual; transmucosal drug delivery; fastdisintegrating tablets; epinephrine; anaphylaxis
4.  An In Vitro Analysis of Disintegration Times of Different Formulations of Olanzapine Orodispersible Tablet: A Preliminary Report 
Drugs in R&d  2013;13:281-288.
Background
Orodispersible tablets (ODTs) are tablet or wafer forms of medication that disintegrate in the mouth, aided only by saliva. ODTs rely on different fast dissolve/disintegration manufacturing technologies.
Objectives
Disintegration time differences for several olanzapine ODT forms were investigated. Risperdal M-Tab® was included as a non-olanzapine ODT comparator.
Research Design and Methods
Eleven olanzapine ODT examples and orodispersible risperidone strengths were evaluated in vitro for formulation composition, manufacturing method, disintegration and dissolution characteristics, and formulation differences in comparison with freeze dried Zydis® ODT. Automated dissolution test equipment captured ODT dissolution rates by measuring real-time release of active ingredient. A high-speed video camera was used to capture tablet disintegration times in warm simulated saliva.
Main Outcome Measure
The main outcome measure was the disintegration and dissolution characteristics of the ODT formulations.
Results
The ODT manufacturing method was associated with time to disintegrate; the fastest were freeze dried tablets, followed by soft compressed tablets and then hard/dense tablets. Olanzapine Zydis® was the only ODT that completely disintegrated in less than 4 s for all strengths (5, 10, 15, and 20 mg), followed by 5-mg Prolanz FAST® (12 s) and then risperidone ODT 4 mg (40 s). Reasons for slow dissolution of the olanzapine generics may include low product potency, excipient binding, excipient solubility, active ingredient particle size and incomplete disintegration.
Conclusions
Differences in the formulation and manufacturing process of olanzapine ODTs appear to have a strong influence on the disintegration time of the active compound; differences that may potentially impact their use in clinical practice.
Electronic supplementary material
The online version of this article (doi:10.1007/s40268-013-0030-8) contains supplementary material, which is available to authorized users.
doi:10.1007/s40268-013-0030-8
PMCID: PMC3879822  PMID: 24170256
5.  An In Vitro Analysis of Disintegration Times of Different Formulations of Olanzapine Orodispersible Tablet: A Preliminary Report 
Drugs in R&D  2013;13(4):281-288.
Background
Orodispersible tablets (ODTs) are tablet or wafer forms of medication that disintegrate in the mouth, aided only by saliva. ODTs rely on different fast dissolve/disintegration manufacturing technologies.
Objectives
Disintegration time differences for several olanzapine ODT forms were investigated. Risperdal M-Tab® was included as a non-olanzapine ODT comparator.
Research Design and Methods
Eleven olanzapine ODT examples and orodispersible risperidone strengths were evaluated in vitro for formulation composition, manufacturing method, disintegration and dissolution characteristics, and formulation differences in comparison with freeze dried Zydis® ODT. Automated dissolution test equipment captured ODT dissolution rates by measuring real-time release of active ingredient. A high-speed video camera was used to capture tablet disintegration times in warm simulated saliva.
Main Outcome Measure
The main outcome measure was the disintegration and dissolution characteristics of the ODT formulations.
Results
The ODT manufacturing method was associated with time to disintegrate; the fastest were freeze dried tablets, followed by soft compressed tablets and then hard/dense tablets. Olanzapine Zydis® was the only ODT that completely disintegrated in less than 4 s for all strengths (5, 10, 15, and 20 mg), followed by 5-mg Prolanz FAST® (12 s) and then risperidone ODT 4 mg (40 s). Reasons for slow dissolution of the olanzapine generics may include low product potency, excipient binding, excipient solubility, active ingredient particle size and incomplete disintegration.
Conclusions
Differences in the formulation and manufacturing process of olanzapine ODTs appear to have a strong influence on the disintegration time of the active compound; differences that may potentially impact their use in clinical practice.
Electronic supplementary material
The online version of this article (doi:10.1007/s40268-013-0030-8) contains supplementary material, which is available to authorized users.
doi:10.1007/s40268-013-0030-8
PMCID: PMC3879822  PMID: 24170256
6.  Maltodextrin: A Novel Excipient Used in Sugar-Based Orally Disintegrating Tablets and Phase Transition Process 
AAPS PharmSciTech  2010;11(2):645-651.
The recent challenge in orally disintegrating tablets (ODT) manufacturing encompasses the compromise between instantaneous disintegration, sufficient hardness, and standard processing equipment. The current investigation constitutes one attempt to fulfill this challenge. Maltodextrin, in the present work, was utilized as a novel excipient to prepare ODT of meclizine. Tablets were prepared by both direct compression and wet granulation techniques. The effect of maltodextrin concentrations on ODT characteristics—manifested as hardness and disintegration time—was studied. The effect of conditioning (40°C and 75% relative humidity) as a post-compression treatment on ODT characteristics was also assessed. Furthermore, maltodextrin-pronounced hardening effect was investigated using differential scanning calorimetry (DSC) and X-ray analysis. Results revealed that in both techniques, rapid disintegration (30–40 s) would be achieved on the cost of tablet hardness (about 1 kg). Post-compression conditioning of tablets resulted in an increase in hardness (3 kg), while keeping rapid disintegration (30–40 s) according to guidance of the FDA for ODT. However, direct compression-conditioning technique exhibited drawbacks of long conditioning time and appearance of the so-called patch effect. These problems were, yet, absent in wet granulation-conditioning technique. DSC and X-ray analysis suggested involvement of glass-elastic deformation in maltodextrin hardening effect. High-performance liquid chromatography analysis of meclizine ODT suggested no degradation of the drug by the applied conditions of temperature and humidity. Overall results proposed that maltodextrin is a promising saccharide for production of ODT with accepted hardness-disintegration time compromise, utilizing standard processing equipment and phenomena of phase transition.
doi:10.1208/s12249-010-9423-y
PMCID: PMC2902317  PMID: 20405257
disintegration time; maltodextrin; meclizine; orally disintegrating tablets; phase transition
7.  Assessment of the pharmaceutical quality of marketed enteric coated pantoprazole sodium sesquihydrate products 
Pantoprazole sodium sesquihydrate (PSS) is a proton pump inhibitor, used in acid-related disorders, like peptic ulcer and gastroesophageal reflux. Increasing the number of pantoprazole containing products in the market, raises questions of its efficacy and generic substitution. The pharmaceutical quality of 6 generic PSS enteric coated tablets in 2 local markets was assessed relative to the innovator product (pantozol®). Uniformity of dosage unit, disintegration and in vitro drug release were determined using United States pharmacopeia for delayed release tablets. The similarity factor (f2) was assessed using the FDA recommended approach (f2 similarity factor). The content uniformity of the innovator product was 98.39% of the labeled claim with RSD value of 1.08%, while the content of generic products ranged from 96.98% to 98.80% with RSD values of 1.24–2.19%. All the products showed no disintegration, cracks or swelling in 0.1 N HCl, except product 1, which showed complete disintegration after 20 min. However, the disintegration of all the products in phosphate buffer met USP requirements. Dissolution of tablets in 0.1 N HCl showed no drug release after 2 h except product 1 in which one tablet showed a drug release more than 10% at acid stage level A1. In addition, three tablets of this product showed dissolution of 45%, 48% and 69% at acid stage level A2. The similarity factor f2 of the products was between 71 and 74 indicating the similarity in dissolution profiles of all the products in accordance to FDA requirements, except product 1 in which f2 value was 18.67.
doi:10.1016/j.jsps.2011.01.001
PMCID: PMC3744956  PMID: 23960750
Generic drugs; Enteric coated tablets; In vitro drug release; Similarity factor; Pantoprazole sodium sesquihydrate
8.  Pharmaceutical quality of seven generic Levodopa/Benserazide products compared with original Madopar® / Prolopa® 
Background
By definition, a generic product is considered interchangeable with the innovator brand product. Controversy exists about interchangeability, and attention is predominantly directed to contaminants. In particular for chronic, degenerative conditions such as in Parkinson’s disease (PD) generic substitution remains debated among physicians, patients and pharmacists. The objective of this study was to compare the pharmaceutical quality of seven generic levodopa/benserazide hydrochloride combination products marketed in Germany with the original product (Madopar® / Prolopa® 125, Roche, Switzerland) in order to evaluate the potential impact of Madopar® generics versus branded products for PD patients and clinicians.
Methods
Madopar® / Prolopa® 125 tablets and capsules were used as reference material. The generic products tested (all 100 mg/25 mg formulations) included four tablet and three capsule formulations. Colour, appearance of powder (capsules), disintegration and dissolution, mass of tablets and fill mass of capsules, content, identity and amounts of impurities were assessed along with standard physical and chemical laboratory tests developed and routinely practiced at Roche facilities. Results were compared to the original “shelf-life” specifications in use by Roche.
Results
Each of the seven generic products had one or two parameters outside the specifications. Deviations for the active ingredients ranged from +8.4% (benserazide) to −7.6% (levodopa) in two tablet formulations. Degradation products were measured in marked excess (+26.5%) in one capsule formulation. Disintegration time and dissolution for levodopa and benserazide hydrochloride at 30 min were within specifications for all seven generic samples analysed, however with some outliers.
Conclusions
Deviations for the active ingredients may go unnoticed by a new user of the generic product, but may entail clinical consequences when switching from original to generic during a long-term therapy. Degradation products may pose a safety concern. Our results should prompt caution when prescribing a generic of Madopar®/Prolopa®, and also invite to further investigations in view of a more comprehensive approach, both pharmaceutical and clinical.
doi:10.1186/2050-6511-14-24
PMCID: PMC3648491  PMID: 23617953
Parkinson’s Disease; Levodopa; Benserazide hydrochloride; Pharmaceutical quality; Generics
9.  Comparative In Vitro Study of Six Carbamazepine Products 
AAPS PharmSciTech  2008;9(2):357-365.
The purpose of present study was to evaluate commercial preparations of carbamazepine tablets with respect to drug release through a defined sequence of experiments using Minitab software. The compliance of products with respect to United States Pharmacopeia (USP) dissolution test and comparison of the products with respect to drug release in different dissolution conditions is reported in the present paper. The different dissolution conditions studied include dissolution medium (1% SLS in purified water, 0.1 N HCl), volume (900 and 1,000 ml), rpm (50 rpm, 75 rpm). Studies indicated that all six products complied with USP dissolution criteria. However, the extent of influence of dissolution conditions on drug release was varied among the products. Distinct dissolution profiles were observed and there was no correlation with disintegration time in certain products. The in vitro dissolution experimentation helped in identifying the discriminatory dissolution conditions and also the formulations that were unaffected with change of dissolution variables. In summary, commercial preparations of carbamazepine vary widely in their dissolution behavior in multi dissolution run experimentation. Identifying this behavior of the products was essential as an in vitro tool for screening a good and a bad formulation.
doi:10.1208/s12249-008-9035-y
PMCID: PMC2976915  PMID: 18431676
carbamazepine; dissolution; drug release; sodium lauryl sulfate
10.  Effect of the mode of incorporation on the disintegrant properties of acid modified water and white yam starches 
Acid modified starches obtained from two species of yam tubers namely white yam – Dioscorearotundata L. and water yam – D. alata L. DIAL2 have been investigated as intra- and extra-granular disintegrants in paracetamol tablet formulations. The native starches were modified by acid hydrolysis and employed as disintegrant at concentrations of 5 and 10% w/w and their disintegrant properties compared with those of corn starch BP. The tensile strength and drug release properties of the tablets, assessed using the disintegration and dissolution (t50 and t80 – time required for 50% and 80% of paracetamol to be released) times, were evaluated. The results showed that the tensile strength and the disintegration and dissolution times of the tablets decreased with increase in the concentration of the starch disintegrants. The acid modified yam starches showed better disintegrant efficiency than corn starch in the tablet formulations. Acid modification appeared to improve the disintegrant efficiency of the yam starches. Furthermore, tablets containing starches incorporated extragranularly showed faster disintegration but lower tensile strength than those containing starches incorporated intragranularly. This emphasizes the importance of the mode of incorporation of starch disintegrant.
doi:10.1016/j.jsps.2011.09.001
PMCID: PMC3745072  PMID: 23960789
Yam starch; Corn starch; Acid modification; Disintegrant properties; Tablets
11.  The suitability of disintegrating force kinetics for studying the effect of manufacturing parameters on spironolactone tablet properties 
AAPS PharmSciTech  2003;4(2):50-56.
The aim of this paper was to study the effect of the granulate properties and tablet compression force on disintegrating force behavior in order to investigate the capability of the disintegrating force to characterize tablets that have the same composition but were manufactured in different conditions. Several tablets containing spironolactone in the external or internal granulated mixture of calcium carbonate and maize starch differing in particle size distribution, were prepared at 3 compression levels. The force developed by tablets during water uptake and disintegration was measured and plotted versus time. The curves obtained were analyzed by the Weibull equation in order to calculate the parameters characterizing the tablet disintegration kinetics. The disintegrating force time parameter, the maximum force developed, and the area under the curve were determined. In general, the reduction of time parameter value and/or the increase in maximum force developed corresponded to an acceleration in tablet disintegration. In addition, the area under the force curve increased in stronger tablets, monitoring in a sensitive way the tablet structural changes introduced by compression force. The results showed that the disintegrating force measurement can detect small changes in the structure of the tablet that cannot be discriminated by pharmacopoeia tests. The effect of manufacturing, in particular compression force, on tablet properties was quantified by the parameters of disintegrating force kinetics.
doi:10.1208/pt040217
PMCID: PMC2750595  PMID: 12916899
disintegrating force; spironolactone; tablet; granulation; compression force
12.  Evaluation of USP apparatus 3 for dissolution testing of immediate-release products 
AAPS PharmSci  2002;4(1):1-5.
We sought to evaluate whether U.S. Pharmacopeia (USP) apparatus 3 can be used as an alternative to USP apparatus 2 for dissolution testing of immediate-release (IR) dosage forms. Highly soluble drugs, metoprolol and ranitidine, and poorly soluble drugs, acyclovir and furosemide, were chosen as model drugs. The dissolution profiles of both innovator and generic IR products were determined using USP apparatus 2 at 50 rpm and apparatus 3 at 5, 15, and 25 dips per minute (dpm). The dissolution profiles from USP apparatus 3 were compared to those from USP apparatus 2 using the f2 similarity test. The dissolution profile from USP apparatus 3 generally depends on the agitation rate, with a faster agitation rate producing a faster dissolution rate. It was found that USP apparatus 3 at the extreme low end of the possible agitation range, such as 5 dpm, gave hydrodynamic conditions equivalent to USP apparatus 2 at 50 rpm. With appropriate agitation rate, USP apparatus 3 can produce similar dissolution profiles to USP apparatus 2 or distinguish dissolution characteristics for the IR products of metoprolol, ranitidine, and acyclovir. Incomplete dissolution was observed for the furosemide tablets using USP apparatus 3. Although it is primarily designed for the release testing of extended-release products, USP apparatus 3 may be used for the dissolution testing of IR products of highly soluble drugs, such as metoprolol and ranitidine, and some IR products of poorly soluble drugs, such as acyclovir. USP apparatus 3 offers the advantages of avoiding cone formation and mimicking the changes in physiochemical conditions and mechanical forces experienced by products in the gastrointestinal tract.
doi:10.1208/ps040101
PMCID: PMC2751286  PMID: 12049485
Dissolution; USP apparatus 2; USP apparatus 3; Immediate-Release; and Product
13.  Hot-Stage Microscopy for Determination of API Particles in a Formulated Tablet 
BioMed Research International  2014;2014:832452.
Although methods exist to readily determine the particle size distribution (PSD) of an active pharmaceutical ingredient (API) before its formulation into a final product, the primary challenge is to develop a method to determine the PSD of APIs in a finished tablet. To address the limitations of existing PSD methods, we used hot-stage microscopy to observe tablet disintegration during temperature change and, thus, reveal the API particles in a tablet. Both mechanical and liquid disintegration were evaluated after we had identified optimum milling time for mechanical disintegration and optimum volume of water for liquid disintegration. In each case, hot-stage micrographs, taken before and after the API melting point, were compared with image analysis software to obtain the PSDs. Then, the PSDs of the APIs from the disintegrated tablets were compared with the PSDs of raw APIs. Good agreement was obtained, thereby confirming the robustness of our methodology. The availability of such a method equips pharmaceutical scientists with an in vitro assessment method that will more reliably determine the PSD of active substances in finished tablets.
doi:10.1155/2014/832452
PMCID: PMC4127278  PMID: 25136629
14.  Porous Magnesium Aluminometasilicate Tablets as Carrier of a Cyclosporine Self-Emulsifying Formulation 
AAPS PharmSciTech  2009;10(4):1388-1395.
The aim of this study was to investigate the ability of liquid loadable tablets (LLT) to be loaded with a self-microemulsifying drug delivery system (SMEDDS) containing cyclosporine (CyA). LLT were prepared by direct compression of the porous carrier magnesium aluminometasilicate and subsequently loaded with SMEDDS by a simple absorption method. SMEDDS was evaluated regarding visual appearance and droplet size distribution after dispersion in aqueous media. The developed SMEDDS was found to be similar to Neoral®. LLT were characterized before and after loading regarding weight variation, tablet hardness, disintegration time, and in vitro drug release. It was found that LLT with high porosities suitable for liquid loading and further processing could be prepared. Adding a tablet disintegrant was found to improve in vitro drug release. Additionally, the volume-based loading capacity of LLT was evaluated and found to be comparable to soft gelatin and hard two-piece capsules. Furthermore, the pharmacokinetic performance of CyA from loaded LLT was tested in two PK-studies in dogs. Absorption of CyA from SMEDDS loaded into LLT was found in the first study to be significantly lower than the absorption of CyA from SMEDDS filled into a capsule. However, addition of a superdisintegrant improved the absorption markedly. The bioavailability of CyA from SMEDDS loaded into disintegrating LLT was found in the second study to be at the same level as from capsule formulation. In conclusion, the LLT technology is therefore seen as a promising alternative way of achieving a solid dosage form from liquid drug delivery systems.
doi:10.1208/s12249-009-9340-0
PMCID: PMC2799606  PMID: 19936938
cyclosporine; drug carrier; liquid loadable tablets; SMEDDS
15.  Miconazole Nitrate Oral Disintegrating Tablets: In Vivo Performance and Stability Study 
AAPS PharmSciTech  2012;13(3):760-771.
The interest in and need for formulating miconazole nitrate (MN), a broad-spectrum antifungal, as an oral disintegrating tablet for treatment of some forms of candidiasis have increased. Formulation of MN in this dosage form will be more advantageous, producing dual effect: local in the buccal cavity and systemic with rapid absorption. Four formulations were prepared utilizing the foam granulation technique. The prepared tablets were characterized by measuring the weight uniformity, thickness, tensile strength, friability, and drug content. In addition, tablet disintegration time, in vitro dissolution, and in vivo disintegration time were also evaluated. Stability testing for the prepared tablets under stress and accelerated conditions in two different packs were investigated. Each pack was incubated at two different elevated temperature and relative humidity (RH), namely 40 ± 2°C/75 ± 5% RH and 50 ± 2°C/75 ± 5% RH. The purpose of the study is to monitor any degradation reactions which will help to predict the shelf life of the product under the defined storage conditions. Finally, in vivo study was performed on the most stable formula to determine its pharmacokinetic parameters. The results revealed that all the prepared tablets showed acceptable tablet characteristics and were stable under the tested conditions. The most stable formula was that containing magnesium stearate as lubricant, hydrophobic Aerosil R972 as glidant, low urea content, mannitol/microcrystalline cellulose ratio 2:1, and 9% Plasdone XL100 as superdisintegrant. The in vivo results revealed that the tested formula showed rapid absorption compared to the physical blend (tmax were 1 and 4 h, respectively), while the extent of absorption was almost the same.
doi:10.1208/s12249-012-9798-z
PMCID: PMC3429679  PMID: 22585373
accelerated stability testing; bioavailability; foam granulation technique; miconazole nitrate; oral disintegrating tablet
16.  The Application of Modified Flow-Through Cell Apparatus for the Assessment of Chlorhexidine Dihydrochloride Release from Lozenges Containing Sorbitol 
AAPS PharmSciTech  2009;10(3):1048-1057.
The objective of this work was to apply a new apparatus for the assay of the drug release from lozenge tablet with a potential use in the treatment of oral candidosis and another conditions connected to microbial etiopathology in the oral cavity or as an antiplaque factor. Also, an approach to comparison of the applied method with the classical paddle apparatus method was performed. Tablets containing chlorhexidine dihydrochloride were formulated with granulated sorbitol of different grades (diameter of 110, 180, 480, and 650 μm, respectively), lactose, and magnesium stearate as excipients. Tablets were obtained through direct compression, and uniformity of weight, friability, breaking strength, disintegration, and release rate were evaluated. The disintegration times ranged between 10 and 21 min. In the next stage of the study, the release of chlorhexidine from lozenges prepared with granulated sorbitol grade 110 μm and different amounts of lactose and magnesium stearate was assessed. Two stages were observed during the release of chlorhexidine dihydrochloride from the lozenges, assayed by the classical paddle apparatus method II USP. In the first stage, release rates were between 2.6 × 10−2 and 4.7 × 10−2 min−1, in the second stage between 1.7 × 10−3 and 7.7 × 10−3 min−1. In the case of the in-house method, the release was near to first-order kinetics through the entire release experiment, with rate constants between 3.6 × 10−2 and 6.6 × 10−2 min−1. The sorbitol granulate of granules with diameter 110 μm was found to be most suitable for the lozenges with chlorhexidine dihydrochloride and lactose. The in-house release method, proposed in this work, seems to be more realistic for the preliminary assessment of predicted drug concentrations in the oral cavity after the intake of a lozenge.
doi:10.1208/s12249-009-9298-y
PMCID: PMC2802162  PMID: 19669894
chlorhexidine; lactose; lozenges; magnesium stearate; release rate; sorbitol
17.  Physical and chemical stability of expired fixed dose combination artemether-lumefantrine in uncontrolled tropical conditions 
Malaria Journal  2009;8:33.
Background
New artemisinin combination therapies pose difficulties of implementation in developing and tropical settings because they have a short shelf-life (two years) relative to the medicines they replace. This limits the reliability and cost of treatment, and the acceptability of this treatment to health care workers. A multi-pronged investigation was made into the chemical and physical stability of fixed dose combination artemether-lumefantrine (FDC-ALU) stored under heterogeneous, uncontrolled African conditions, to probe if a shelf-life extension might be possible.
Methods
Seventy samples of expired FDC-ALU were collected from private pharmacies and malaria researchers in seven African countries. The samples were subjected to thin-layer chromatography (TLC), disintegration testing, and near infrared Raman spectrometry for ascertainment of active ingredients, tablet integrity, and chemical degradation of the tablet formulation including both active ingredients and excipients.
Results
Seventy samples of FDC-ALU were tested in July 2008, between one and 58 months post-expiry. 68 of 70 (97%) samples passed TLC, disintegration and Raman spectrometry testing, including eight samples that were post-expiry by 20 months or longer. A weak linear association (R2 = 0.33) was observed between the age of samples and their state of degradation relative to brand-identical samples on Raman spectrometry. Sixty-eight samples were retested in February 2009 using Raman spectrometry, between eight and 65 months post-expiry. 66 of 68 (97%) samples passed Raman spectrometry retesting. An unexpected observation about African drug logistics was made in three batches of FDC-ALU, which had been sold into the public sector at concessional pricing in accordance with a World Health Organization (WHO) agreement, and which were illegally diverted to the private sector where they were sold for profit.
Conclusion
The data indicate that FDC-ALU is chemically and physically stable well beyond its stated shelf-life in uncontrolled, tropical conditions. While these data are not themselves sufficient, it is strongly suggested that a re-evaluation of the two-year shelf-life by drug regulatory authorities is warranted.
doi:10.1186/1475-2875-8-33
PMCID: PMC2649943  PMID: 19243589
18.  STUDIES IN ATYPICAL FORMS OF TUBERCLE BACILLI ISOLATED DIRECTLY FROM THE HUMAN TISSUES IN CASES OF PRIMARY CERVICAL ADENITIS  
The four cultures which form the basis of this communication were recovered from peculiar cases of primary cervical adenitis in man, three of which terminated fatally of disseminated acute miliary tuberculosis in four to six weeks. A careful comparative study shows that Culture II corresponds closely with the "human" and Culture IV with the "bovine" type of tubercle bacilli; while Cultures I and III present variations from the standard types and are to be retarded as "intermediate" or "atypical" forms. Culture I is of unusual interest because of its remarkable variations. The clinical picture of the case, the rapid course of the infection, the enormous number of the bacilli in the tissue, their tendency to occur in "heaps" like the leprosy bacillus, the high degree of virulence alike for rabbits and guinea-pigs, the production of lesions in chickens, the case of cultivation and the prolonged viability under unfavorable conditions, all mark the organism as a decided atypical form of tubercle bacillus in man. The prolonged viability, the production of lesions in the chicken and the great profusion of bacillary growth in the tissues would indicate an avian type. Though for years the reaction curve was atypical it has since changed completely to the "avian" curve. In this connection it is of interest to note that L. Rabinowitsch (3) states that she has isolated avian tubercle bacilli from two cases of tuberculosis in man. Cultures II and III undoubtedly belong to the human type of the tubercle family though they were under cultivation and were repeatedly tested upon glycerine broth over a period of months before their identity was definitely established. Culture IV completely corresponds in growth and reaction in glycerine bouillon to the bovine strain; however, it manifests a low degree of virulence for rabbits which is exceptional for bovine cultures. The old belief that bovine bacilli are more slender and beaded in the tissues and are thicker and shorter in culture than the human type, I have not been able to confirm. The morphological characters of the different cultures here reported were so inconstant that no reliance could be placed on this feature as an aid in differentiation. Outside of the animal body it would seem that the differences in size and character of the individual bacilli depend largely on the kind and reaction of the medium, whilst in the animal body they are influenced by their situation and the resistance of the host. The nature of the growth of these tubercle cultures varies for the same culture even under apparently identical conditions. The character of the growth was never an indication of the type of the culture, It was common to obtain two distinct types of growth on the same flask of bouillon, i. e., a portion of the surface would be covered with a heavy and uniformly granular layer of closely packed wax-like colonies twice the size of an ordinary pin's head, while the other portion would be a dense homogeneous layer with the typical depressed blisters. The rapidity of growth also varied greatly for the same culture. Often in a series of twelve or more bouillon flasks which were prepared alike and inoculated with the same culture, some would cover the surface in eight days to two weeks, others would take four to six weeks, still others two to three months. It was thought in the beginning of the work that this variation might depend on the amount of oxygen within the flask or on the change in reaction in the bouillon, but further tests proved that neither of these influenced the rate of growth in any way. It would occur in loosely corked flasks as well as in those that were sealed, and in flasks where the reaction was neutral, acid or slightly alkaline. It would seem that these changes are by no means specific for any group of the tubercle bacilli but a property possessed by them all. The growth of the cultures on solid medium showed approximately the same variation as that from the surface of the glycerine bouillon. The wax-like colonies described by L. Rabinowitsch (3) as characteristic for avian tubercle bacilli were noted at times for all of the cultures. On the modified egg mixture the growth was always more rapid and profuse than on any other medium. I found this egg medium more certain than any other for the direct recovery of the tubercle bacillus from the tissues. Where it was desired to recover the culture from the animal tissues with certainty and celerity it had no equal. Occasionally in seven days after the inoculation of the tuberculous gland material the growth was sufficiently advanced to transplant to the bouillon flasks. The glycerine bouillon test serves admirably to distinguish between the human, bovine and avian types of tubercle bacilli. It is also of value in the determination of degrees of adaptation in man for bacilli of the lower host-species, and in the recognition of "intermediate" types. The test to be of differential value requires repeated application and careful control over a period of months. Some freshly isolated cultures may produce their specific reaction curve in glycerine bouillon within a few weeks. On the other hand the same culture may fail to give its characteristic reaction or any alteration in the glycerine bouillon for several months though the growth has been luxuriant and complete. The rise in acidity that occurs in glycerine bouillon for the human type of tubercle bacilli is due to a specific action on the glycerine of the products of disintegration of bacilli (autolysis); with the bovine and avian types the products of bacillary disintegration have no action on the glycerine. The fall in acidity which occurs for all three types of the tubercle bacillus is due to the products of metabolic activity.
PMCID: PMC2124717  PMID: 19867256
19.  Comparative evaluation of tableting compression behaviors by methods of internal and external lubricant addition: Inhibition of enzymatic activity of trypsin preparation by using external lubricant addition during the tableting compression process 
AAPS PharmSci  2001;3(3):32-42.
This study evaluated tableting compression by using internal and external lubricant addition. The effect of lubricant addition on the enzymatic activity of trypsin, which was used as a model drug during the tableting compression process, was also investigated. The powder mixture (2% crystalline trypsin, 58% crystalline lactose, and 40% microcrystalline cellulose) was kneaded with 5% hydroxypropyl cellulose aqueous solution and then granulated using an extruding granulator equipped with a 0.5-mm mesh screen at 20 rpm. After drying, the sample granules were passed through a 10-mesh screen (1680 μm). A 200-mg sample was compressed by using 8-mm punches and dies at 49, 98, 196, or 388 MPa (Mega Pascal) at a speed of 25 mm/min. The external lubricant compression was performed using granules without lubricant in the punches and dies. The granules were already dry coated by the lubricant. In contrast, the internal lubricant compression was performed using sample granules (without dry coating) containing 0.5% lubricant. At 98 MPa, for example, the compression level using the external lubricant addition method was about 13% higher than that for internal addition. The significantly higher compressing energy was also observed at other MPas. By comparison, the friction energy for the external addition method calculated based on upper and lower compression forces was only slightly larger. The hardness of tablets prepared using the internal addition method was 34% to 48% lower than that for the external addition method. The total pore volume of the tablet prepared using the external addition method was significantly higher. The maximum ejection pressure using the no-addition method (ie, the tablet was prepared using neither dry-coated granules nor added lubricant) was significantly higher than that of other addition methods. The order was as follows: no addition, external addition, and then internal addition. The ejection energy (EE) for internal addition was the lowest; for no addition, EE was the highest. In the dissolution test, the tablets obtained using external addition immediately disintegrated and showed faster drug release than those prepared using internal addition. This result occurred because the water penetration rate of the tablet using the external addition was much higher. The trypsin activity in tablets prepared using the external addition method was significantly higher than that produced using the internal addition method at the same pressure. All these results suggest that the external addition method might produce a fast-dissolution tablet. Because the drug will be compressed using low pressure only, an unstable bulk drug may be tableted without losing potency.
doi:10.1208/ps030320
PMCID: PMC2751015  PMID: 11741271
Tableting; Trypsin; Preparation; Compression; Dissolution
20.  Acid-treated yeast cell wall as a binder displaying function of disintegrant 
AAPS PharmSciTech  2003;4(3):94-100.
This investigation examined the application of acid-treated yeast cell wall (AYC) as a binder functioning as a disintegrant. Acetylsalicylic acid (ASA) was granulated with AYC, hydroxypropylcellulose (HPC), polyvinylpyrrolidone (PVP), or pullulan (PUL) and compressed into a tablet in the absence of disintegrant. Particle size and angle of repose of the granules, tensile strength, disintegration time, and water absorption behavior of the tablets and ASA release profiles from the tablets were measured. The surface of AYC-granules was observed with a scanning electron microscope. As was the case with the granules of HPC, PVP, or PUL, D50 of the granules of AYC increased with increasing AYC addition percentage, indicating that it is possible to granulate ASA with AYC. Tablets incorporating HPC, PVP, and PUL failed to disintegrate within 30 minutes at all percentages of binder addition because in the case of the HPC, PVP, or PUL tablets in the dissolution medium, water scarcely penetrated into the inner region of the tablet, causing no disintegration. In the case of the AYC tablets, disintegration was not detected at 3% or less of AYC. When AYC was equal to or greater than 5%, AYC tablets disintegrated in approximately 4 minutes and rapid ASA release from the tablets was observed. These results may have been caused by the following. In the case of the AYC 3% granules, ungranulated aspirin powder remained, but in the case of the AYC 5% granules, ASA powder was granulated and covered with AYC. Water absorption was observed initially; however, a plateau was reached in the case of the AYC 3%-tablet. In contrast, in the cases of the AYC 5% and more tablets, water absorption was greater and increased with time. The angle of repose of the AYC 5% granules was 25.7°, which represented high fluidity. The tablets produced by compressing the granules demonstrated sufficient tensile strength greater than 0.8 MPa. The tablets rapidly disintegrated and rapid ASA release was obtained. AYC functioned as a binder at granulation; additionally, AYC served as a disintegrant in the dissolution of drug from the tablets. These results indicate that AYC affords high utility as a unique pharmaceutical additive possessing contrary functions such as binding and disintegration.
doi:10.1208/pt040341
PMCID: PMC2750634  PMID: 14621973
acid-treated yeast cell wall; pharmaceutical additive; binder; disintegrant; granulation; swelling
21.  Formulation Development and Evaluation of Fast Disintegrating Tablets of Salbutamol Sulphate for Respiratory Disorders 
ISRN Pharmaceutics  2013;2013:674507.
Recent developments in fast disintegrating tablets have brought convenience in dosing to pediatric and elderly patients who have trouble in swallowing tablets. The objective of the present study was to prepare the fast disintegrating tablet of salbutamol sulphate for respiratory disorders for pediatrics. As precision of dosing and patient's compliance become important prerequisites for a long-term treatment, there is a need to develop a formulation for this drug which overcomes problems such as difficulty in swallowing, inconvenience in administration while travelling, and patient's acceptability. Hence, the present investigation were undertaken with a view to develop a fast disintegrating tablet of salbutamol sulphate which offers a new range of products having desired characteristics and intended benefits. Superdisintegrants such as sodium starch glycolate was optimized. Different binders were optimized along with optimized superdisintegrant concentration. The tablets were prepared by direct compression technique. The tablets were evaluated for hardness, friability, weight variation, wetting time, disintegration time, and uniformity of content. Optimized formulation was evaluated by in vitro dissolution test, drug-excipient compatibility, and accelerated stability study. It was concluded that fast disintegrating tablets of salbutamol sulphate were formulated successfully with desired characteristics which disintegrated rapidly; provided rapid onset of action; and enhanced the patient convenience and compliance.
doi:10.1155/2013/674507
PMCID: PMC3727126  PMID: 23956881
22.  Effect of Sorbed Water on Disintegrant Performance of Four Brands of Polacrilin Potassium NF 
AAPS PharmSciTech  2011;13(1):24-34.
Polacrilin Potassium NF is a commonly used weak cation exchange resin disintegrant in pharmaceutical tablets. The objective of this research was to evaluate the effects of sorbed moisture on physical characteristics and disintegrant performance of four brands of Polacrilin Potassium NF. The disintegrants were stored in five different relative humidity chambers and their dynamic vapor adsorption–desorption analysis, effect of moisture on their compressibility, compactability, particle size, morphology, water uptake rate, and disintegration ability were studied. Moisture seemed to plasticize the disintegrants, reducing their yield pressures. However, certain optimum amount of moisture was found to be useful in increasing the compactablity of the tablets containing disintegrants. The tablets, however, lost their tensile strengths beyond this optimum moisture content. Moisture caused two brands of the disintegrants to swell; however, two other brands aggregated upon exposure to moisture. Swelling without aggregation increased the water uptake, and in turn the disintegrant performance. However, aggregation probably reduced the porosities of the disintegrants, reducing their water uptake rate and disintegrant performance. Different brands of Polacrilin Potassium NF differed in the abilities to withstand the effects of moisture on their functionality. Effect of moisture on disintegrant performance of Polacrilin Potassium NF needs to be considered before its use in tablets made by wet granulation.
doi:10.1208/s12249-011-9717-8
PMCID: PMC3299451  PMID: 22068291
disintegrant performance; effect of moisture; functionality; ion exchange resins; physical characterization; polacrilin potassium NF; sorbed water; tablet disintegrants
23.  Differences in In Vitro Disintegration Time among Canadian Brand and Generic Bisphosphonates 
Journal of Osteoporosis  2014;2014:420451.
The objective of this study was to compare the disintegration times among Canadian-marketed brand (alendronate 70 mg, alendronate 70 mg plus vitamin D 5600 IU, and risedronate 35 mg) and generic (Novo-alendronate 70 mg and Apo-alendronate 70 mg) once-weekly dosed bisphosphonates. All disintegration tests were performed with a Vanderkamp Disintegration Tester. Disintegration was deemed to have occurred when no residue of the tablet, except fragments of insoluble coating or capsule shell, was visible. Eighteen to 20 samples were tested for each bisphosphonate group. The mean (±standard deviation) disintegration times were significantly (P < 0.05) faster for Apo-alendronate (26 ± 5.6 seconds) and Novo-alendronate (13 ± 1.1 seconds) as compared to brand alendronate (147 ± 50.5 seconds), brand alendronate plus vitamin D (378 ± 60.5 seconds), or brand risedronate (101 ± 20.6 seconds). The significantly faster disintegration of the generic tablets as compared to the brand bisphosphonates may have concerning safety and effectiveness implications for patients administering these therapies.
doi:10.1155/2014/420451
PMCID: PMC4202245  PMID: 25349772
24.  The Quality Control Assessment of Commercially Available Coenzyme Q10-Containing Dietary and Health Supplements in Japan 
Coenzyme Q10 (CoQ10) has been widely commercially available in Japan as a dietary and health supplement since 2001 and is used for the prevention of lifestyle-related diseases induced by free radicals and aging. We evaluated CoQ10 supplements to ensure that these supplements can be used effectively and safely. Commercially available products were selected and assessed by the quality control tests specified in the Japanese Pharmacopoeia XV. When the disintegration time of CoQ10 supplements was measured, a few tested supplements did not completely disintegrate even after incubation in water for an hour at 37°C. In the content test, many samples were well controlled. However, a few supplements showed low recovery rates of CoQ10 as compared to manufacturer’s indicated contents. Among soft capsule and liquid supplements, the reduced form of CoQ10 (H2CoQ10), as well as the oxidized form, was detected by HPLC with electrochemical detector. The results for experimental formulated CoQ10 supplements demonstrated that H2CoQ10 was produced by the interaction of CoQ10 with vitamins E and/or C. From these results, we concluded that quality varied considerably among the many supplement brands containing CoQ10. Additionally, we also demonstrated that H2CoQ10 can be detected in some foods as well as in CoQ10 supplements.
doi:10.3164/jcbn.2007017
PMCID: PMC2170950  PMID: 18193106
coenzyme Q10; ubiqinol-10; quality control; dietary and health supplement; food
25.  The influence of swelling capacity of superdisintegrants in different pH media on the dissolution of hydrochlorothiazide from directly compressed tablets 
AAPS PharmSciTech  2005;6(1):E120-E126.
The purpose of this study was to investigate the efficiency of superdisintegrants in promoting tablet disintegration and drug dissolution under varied media pH. Significant reductions in the rate and extent of water uptake and swelling were observed for both sodium starch glycolate (Primojel) and croscarmellose sodium (Ac-Di-Sol) in an acidic medium (0.1 N HCl) but not for crospovidone NF (Polyplasdone XL10), a nonionic polymer. When Primojel and Ac-Di-Sol were incorporated in model formulations, a significant increase in tablet disintegration time was observed for slowly disintegrating tablets (lactose-based tablets) but not for the rapidly disintegrating tablets (dicalcium phosphate-based tablets). The dissolution rate of the model drug, hydrochlorothiazide, was found highly dependent on both tablet disintegration efficiency and the solubility of base material(s) in the testing medium. A laser diffraction particle size analyzer proved to be an effective tool for determining the intrinsic swelling of disintegrant particles in different media. Water uptake and swelling were confirmed as 2 important functions of superdisintegrants. The reduced water uptake and swelling capacity of disintegrants containing ionizable substituents in an acidic medium can potentially jeopardize their efficiency in promoting tablet disintegration and the drug dissolution rate.
doi:10.1208/pt060119
PMCID: PMC2750420  PMID: 16353956
superdisintegrants; particle swelling; liquid uptake; disintegration medium pH; dissolution medium pH; hydrochlorothiazide

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