Potential Use of Magnesium Oxide as an Excipient to Maintain the Hardness of Orally Disintegrating Tablets during Unpackaged Storage.

This study aimed to clarify the effects of magnesium oxide (MgO) on the hardness of orally disintegrating tablets (ODTs) during storage. ODTs containing a range of MgO concentrations were prepared by direct powder compression and stored for up to 4 weeks in an unpackaged condition at 40°C, with 75% relative humidity. Tablets that did not contain MgO showed a significant decrease in hardness after one week in storage, while those containing MgO at a mass fraction of ≥4% maintained their hardness for up to 4 weeks. The tablet disintegration times after storage were equivalent to those observed before storage (approximately 30 s), regardless of the MgO level. Furthermore, the dissolution behavior of a model drug (acetaminophen) from the ODTs was not affected by the level of MgO. These findings revealed that the addition of MgO suppressed the reduction in ODT hardness during storage in the unpackaged state, without delaying tablet disintegration or inhibiting drug release.

Utility of Microcrystalline Cellulose for Improving Drug Content Uniformity in Tablet Manufacturing Using Direct Powder Compression.

Direct powder compression is the simplest tablet manufacturing method. However, segregation occurs when the drug content is low. It is difficult to assure drug content uniformity in these cases. In this study, we evaluated microcrystalline cellulose (MCC) as a segregation inhibitor in pharmaceutical powders. We assessed the influence of MCC concentration and mixing time on the physical properties of tablets. The tablet formulation comprised acetaminophen, lactose hydrate, cornstarch, MCC (0%, 10%, or 20%), croscarmellose sodium, and magnesium stearate (Mg-St). All powders except Mg-St were premixed for 5, 15, or 25 min. Mg-St was then added and mixed for 5 min to prepare nine pharmaceutical powders. Flowability index and practical angle of internal friction were measured. Tablets were also prepared, and their weight variation, hardness, friability, disintegration time, and drug content variation were evaluated. MCC slightly decreased pharmaceutical powder flowability. Tablet hardness increased and disintegration time decreased with increasing MCC concentration. MCC mixed for ≥ 15 min also significantly lowered drug content variation. A contour plot was prepared to assess the effect of MCC concentration and mixing time on the physical properties of tablets. It was determined that tablets with 50-80 N hardness, ≤ 3.5 min disintegration time, and ≤ 3% drug content variation can be prepared when MCC concentration is 6.5-8.5% and the mixing time is 19-24 min. Therefore, MCC is effective as a segregation inhibitor, and the addition of MCC to tablet formulation improves drug content uniformity.

Correction to: Preparation of Controlled-Release Particles Based on Spherical Porous Silica Used as the Drug Carrier by the Dry Coating Method.

In the present notation, the formula names and the formulas (page 7, left column, lines 20-21) do not correspond to each other. It is a completely incorrect description, due to a typesetting mistake by the publisher. See below for details. The original article has been corrected.

Preparation of Controlled-Release Particles Based on Spherical Porous Silica Used as the Drug Carrier by the Dry Coating Method.

A controlled-release formulation is a dosage form that could improve a patient's quality of life by reducing the frequency of administration, while ensuring the continued effect of the medicine and reducing the side effects. To prepare these controlled-release particles, a wet coating method in which a drug is coated with a controlled-release material using water or an organic solvent is used, but with this method, the coating process is very time-consuming and requires large amounts of energy for the drying phase. In addition, contact with water or an organic solvent may cause problems such as alteration of the drug. Therefore, the use of a dry coating method has attracted attention as a means of overcoming these issues. However, since the drug is fixed to the surface of a core particle, it is necessary to further coat it with a water-soluble material. We used spherical porous silica (SPS) particles, considering that the drug fixation via a water-soluble material would not be necessary if the drug were to be placed in the pores of these particles. We used SPS filled with theophylline (TP), a model drug, as the core particles. To prepare controlled-release particles (CRP), a controlled-release layer consisting of hydrogenated castor oil (HCO) was applied to the core particle surface by a dry coating method. The paddle method using 1% w/v polysorbate 80 solution as the test medium was employed to estimate the TP dissolution rate of the resulting CRPs. The 50% dissolution time of TP extended from 14 to 405 min with increasing the amount of the coated HCO. The Korsmeyer-Peppas model applied to the TP dissolution behavior yielded an n value of around 1. Moreover, the K value was comparable with the case in which a zero-order model was applied. It is thought that the dissolution of TP from CRPs will conform to the zero-order model.

Evaluation of Sucrose Fatty Acid Esters as Lubricants in Tablet Manufacturing.

Lubricants are essential additives in tablet formulations. Magnesium stearate (Mg-St) is the most commonly used lubricant in tableting. Here, we used sucrose fatty acid ester (SE) as an additive to manufacture tablets by direct compression. We evaluated the effects of hydrophile-lipophile balance (HLB) and the amount of SE on the flowability of a pharmaceutical powder using angle of repose and practical angle of internal friction measurements. In addition, we investigated the effects of SE on tablet properties. When SEs with an HLB ≥3 were added, the angle of repose was approximately the same as that of a pharmaceutical powder containing Mg-St, with no major differences in flowability. However, the practical angle of internal friction became closer to pharmaceutical powder containing Mg-St as HLB decreased. As HLB increased, the practical angle of internal friction approached the value of additive-free pharmaceutical powder. Tablets containing 2.0% Mg-St had a mean hardness of 40 N and disintegrated in approximately 6 min, whereas tablets containing 2.0% SE (low HLB) had a mean hardness of approximately ≥80 N and disintegrated within 3 min. The results indicate that SEs can be used as lubricants in tablet production by direct compression and to reduce problems associated with the use of Mg-St. In particular, we suggest that SEs with low HLB values can be used as excipients to achieve high tablet hardness and short disintegration time.

Setting Ideal Lubricant Mixing Time for Manufacturing Tablets by Evaluating Powder Flowability.

We investigated the effectiveness of using Carr's flowability index (FI) and practical angle of internal friction (Φ) as indexes for setting the target Mg-St mixing time needed for preparing tablets with the target physical properties. We used FI as a measure of flowability under non-loaded conditions, and Φ as a measure of flowability under loaded conditions for pharmaceutical powders undergoing direct compression with varying concentrations of Mg-St and mixing times. We evaluated the relationship between Mg-St mixing conditions and pharmaceutical powder flowability, analyzed the correlation between the physical properties of the tablets (i.e., tablet weight variation, drug content uniformity, hardness, friability, and disintegration time of tablets prepared using the pharmaceutical powder), and studied the effect of Mg-St mixing conditions and pharmaceutical powder flowability on tablet properties. Mg-St mixing time highly correlated with pharmaceutical powder FI (R 2 = 0.883) while Mg-St concentration has low correlation with FI, and FI highly correlated with the physical properties of the tablet (R 2 values: weight variation 0.509, drug content variation 0.314, hardness 0.525, friability 0.477, and disintegration time 0.346). Therefore, using pharmaceutical powder FI as an index could enable prediction of the physical properties of a tablet without the need for tableting, and setting the Mg-St mixing time by using pharmaceutical powder FI could enable preparation of tablets with the target physical properties. Thus, the FI of the intermediate product (i.e., pharmaceutical powder) is an effective index for controlling the physical properties of the finished tablet.

Mechanism by Which Magnesium Oxide Suppresses Tablet Hardness Reduction during Storage.

This study investigated how the inclusion of magnesium oxide (MgO) maintained tablet hardness during storage in an unpackaged state. Tablets were prepared with a range of MgO levels and stored at 40°C with 75% relative humidity for up to 14 d. The hardness of tablets prepared without MgO decreased over time. The amount of added MgO was positively associated with tablet hardness and mass from an early stage during storage. Investigation of the water sorption properties of the tablet components showed that carmellose water sorption correlated positively with the relative humidity, while MgO absorbed and retained moisture, even when the relative humidity was reduced. In tablets prepared using only MgO, a petal- or plate-like material was observed during storage. Fourier transform infrared spectrophotometry showed that this material was hydromagnesite, produced when MgO reacts with water and CO2. The estimated level of hydromagnesite at each time-point showed a significant negative correlation with tablet porosity. These results suggested that MgO suppressed storage-associated softening by absorbing moisture from the environment. The conversion of MgO to hydromagnesite results in solid bridge formation between the powder particles comprising the tablets, suppressing the storage-related increase in volume and increasing tablet hardness.

Predicting the Occurrence of Sticking during Tablet Production by Shear Testing of a Pharmaceutical Powder.

Sticking is a failure of pharmaceutical production that occurs when a powder containing a large amount of adhesive is being tableted. This is most frequently observed when long-term tableting is carried out, making it extremely difficult to predict its occurrence during the tablet formula design stage. The efficiency of the pharmaceutical production process could be improved if it were possible to predict whether a particular formulation was likely to stick during tableting. To address this issue, in the present study we prepared tablets composed of blended ibuprofen (Ibu), a highly adhesive drug, and measured the degree of adherence of powder particles to the surface of the tablet punch. We also measured the shear stress of the powder to determine the practical angle of internal friction (Φp) of the powder bed as well as the angle of wall friction (Φw) relative to the punch surface. These values were used to define a sticking index (SI), which showed a high correlation with the amount of Ibu that adhered to the punch during tableting; sticking occurred at SI >0.3. When the amount of lubricant added to the formulation was changed to yield tablets exhibiting different SI values without changing the compounding ratio, sticking did not occur at SI ≤0.3. These results suggest that determining the SI of a pharmaceutical powder before tableting allows prediction of the likelihood of sticking during tableting.

Preparation of Controlled-Release Fine Particles Using a Dry Coating Method.

Wet coating methods use organic solvents to prepare layered particles that provide controlled-release medications. However, this approach has disadvantages in that it can cause particle agglomeration, reduce pharmaceutical stability, and leave residual organic solvents. We used a dry coating method to overcome these issues. Fine particles (less than 50 µm in diameter) of controlled-release theophylline were created using theophylline (TP; model drug), polyethylene glycol 20,000 (PEG; drug fixative), hydrogenated castor oil (HCO; controlled-release material), hydrogenated rapeseed oil (HRSO; controlled-release material), and cornstarch (CS; core particle). An ultrahigh-speed mixer was employed to mix TP and CS for 5 min at 28,000 rpm. Subsequent addition of PEG produced single-core particles with a drug reservoir coating. Addition of HCO and HRSO to these particles produced a controlled-release layer on their surface, resulting in less than 10% TP dissolution after 8 h. We successfully demonstrated that this dry coating method could be used to coat 16-µm CS particles with a drug reservoir layer and a controlled-release layer, producing multi-layer coated single-core particles that were less than 50 µm in diameter. These can be used to prepare controlled-release tablets, capsules, and orally disintegrating tablets.

Triterpenoid saponins from Echinopsis macrogona (Cactaceae).

Triterpene saponins, pachanosides C1, E1, F1 and G1 (1-4), and bridgesides A1, C1, C2, D1, D2, E1 and E2 (5-11) were isolated from Echinopsis macrogona. Compounds 1-4 were saponins with pachanane type triterpene saponins, while the others (5-11) were oleanane type triterpene saponins. While the aglycones of 2-4 and 8-11 were hitherto unknown, the structure of pachanol C was revised in this paper. Their structures were elucidated on the basis of chemical and physicochemical evidence.

Preparation of polymeric submicron particle-containing microparticles using a 4-fluid nozzle spray drier.

PURPOSE: We studied a novel method for preparing polymeric submicron particle-containing microparticles using a 4-fluid nozzle spray drier. METHOD: Ethylcellulose (EC) and poly(lactic-co-glycolic acid) (PLGA), either alone or in combination with polyethylenimine (PEI), were used as polymers to produce submicron particles, and mannitol (MAN) was used as a water-soluble carrier for the microparticles. The polymer and MAN solutions were supplied through different liquid passages of a 4-fluid nozzle and then dried to obtain MAN microparticles containing EC or PLGA submicron particles. The polymer/MAN ratio was controlled by changing the concentration of the polymer and MAN solutions. EC or PLGA microparticles were observed via scanning electron microscopy, and the size of microparticles was determined by image analysis. The particle size distribution of EC or PLGA submicron particles was measured with a super dynamic light scattering spectrophotometer. RESULTS: The method generated submicron-sized (<1 microm) particles of EC and PLGA. The mean diameters of EC and PLGA particles at a polymer/MAN ratio of 1:10 were 631 and 490 nm, respectively. The mean diameter of PLGA particles decreased as the PLGA/MAN ratio was reduced, reaching approximately 200 nm at a PLGA/MAN ratio of 1:100. The mean diameter of PLGA/PEI particles at PLGA/PEI/MAN ratios of 1:0.5:10 and 1:0.5:100 were 525 and 223 nm, respectively, and their zeta potentials were +50.8 and +58.2 mV, respectively. The size of EC submicron particles could be controlled by varying the spray conditions. CONCLUSIONS: This study demonstrated that it is possible to prepare polymeric submicron particles dispersed in MAN microparticles in a single process using the 4-fluid nozzle spray drying method. Cationic PLGA particles with a diameter of approximately 200 nm could be prepared by adding PEI, suggesting the possibility of its use as a carrier for delivering DNA into cells. The precipitation of EC may occur by the mutual dispersion and mixing of solvents after collision of EC and MAN mists by antisolvent effect, thereby producing MAN microparticles containing EC submicron particles.

Controlled release of drug via methylcellulose-carboxyvinylpolymer interpolymer complex solid dispersion.

The purpose of this research was to examine the controlled release of phenacetin (PHE) from solid dispersion by the formation of an interpolymer complex between methylcellulose (MC) and carboxyvinylpolymer (CP). The PHE/polymer composition ratio was fixed at 20:80 (w/w) in the solid dispersion. The effect of the MC/CP ratio and molecular weight of MC on the PHE release was studied. The release of PHE from the solid-dispersion granules depended on the MC/CP ratio, with a ratio of 50:50 giving the lowest rate of release. In aqueous solution, this MC/CP ratio resulted in the lowest transmittance, suggesting a maximal extent of interpolymer complex formation between MC and CP. Furthermore, at a MC/CP ratio of 50:50, the release of PHE from the solid dispersion granules decreased as the molecular weight of the MC increased, reaching a plateau at molecular weights >or=180,000. The contributions of diffusion and polymer relaxation to PHE release increased as the molecular weight of the MC increased. This study shows that it is feasible to control the release of PHE from MC-CP solid dispersion granules by modulating complex formation between MC and CP, which can be accomplished by altering the MC/CP ratio and the molecular weight of MC.

Preparation of two-drug composite microparticles to improve the dissolution of insoluble drug in water for use with a 4-fluid nozzle spray drier.

In this study, we used a novel 4-fluid nozzle spray drier to prepare composite microparticles of a water-insoluble drug, flurbiprofen (FP), and a water-soluble drug, sodium salicylate (SS), for the purpose of improving the water solubility of FP. An ethanol solution of FP and an aqueous SS solution were simultaneously introduced through different liquid passages in the 4-fluid nozzle spray drier and then spray-dried. Quantitative elemental analysis suggested that the FP/SS ratio in each composite microparticle was nearly the same as the formulation ratio. We also found that SS and FP exist in a low crystallinity state in the composite particles. Release of FP from dissolved composite microparticles was markedly improved because of an increase in the effective surface area following rapid dissolution of SS. This study shows that it is possible to prepare FP-SS composite microparticles using a 4-fluid nozzle spray drier in single process and that this can improve the ability of FP to dissolve in water.

Acid-treated yeast cell wall as a binder displaying function of disintegrant.

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 degrees, 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.

Assessment of tableting properties using infinitesimal quantities of powdered medicine.

In the early stage of new drug candidate development, the available quantity of drug substance is limited. In order to carry out preformulation studies of tablets in this stage, a static compression test was carried out with infinitesimal quantity of powder sample using the new Micro Powder Characterizer device. Aspirin, phenacetin, ascorbic acid and ethenzamide were used as model drugs. In this study, the possibility of use of the Micro Powder Characterizer as a device for estimating the tableting properties of each powder sample such as stress displacement curves, tablet tensile strength, stress relaxation rate, and ejection energy was evaluated. In addition, the differences between the Micro Powder Characterizer and the traditional large-scale compression testing machine were compared. It was found that tableting properties could be estimated by the Micro Powder Characterizer, and that the quantity required to estimate tableting properties was approximately 10 mg per measurement. The results were nearly equal to those obtained with the traditional large-scale compression testing machine. This technique thus appears to be useful for early-stage preformulation studies of new drug candidates.

Effect of shape of sodium salicylate particles on physical property and in vitro aerosol performance of granules prepared by pressure swing granulation method.

The purpose of this research was to investigate the effect of the shape of sodium salicylate (SS) particles on the physical properties as well as the in vitro aerosol performance of the granules granulated by the pressure swing granulation method. SS was pulverized with a jet mill (JM) to prepare the distorted particles, and SS aqueous solution was spray dried (SD) to prepare the nearly spherical particles. The particle size distribution, crushing strength, and pore size distribution of the granules were measured. The adhesive force of the primary particles in the granules was calculated according to Rumpf's equation. The in vitro aerosol performance of the granules was evaluated using a cascade impactor. Both JM and SD particles can be spherically granulated by the pressure swing granulation method without the use of a binder. The size of SD granules was smaller than that of JM granules. Although the crushing strength of the JM and SD granules is almost the same, the internal structures of JM granules and SD granules were found to differ, and the SD particles appear to have been condensed uniformly, resulting in a nearly spherical shape. In the inhalation investigation, the percentage of SS particles of appropriate size delivered to the region for treatment was noticeably higher for SD granules than for JM granules. This finding might be because the adhesive force of the SD primary particles was smaller than that of the JM primary particles in the granules and because the SD granules could be easily separated by air current to obtain the primary particles.

Application of acid-treated yeast cell wall (AYC) as a pharmaceutical additive. III. AYC aqueous coating onto granules and film formation mechanism of AYC.

From the viewpoint of effective utilization of natural resources and development of new pharmaceutical materials, acid-treated yeast cell wall (AYC) was prepared via a novel approach involving acidification of brewers' yeast cell wall. AYC aqueous dispersion containing 5% (w/v) AYC and 0.5% (w/v) glycerol was prepared. Subsequently, AYC was coated onto core granules containing acetaminophen (AAP). Spray mist size under various spray conditions and viscosity of the AYC aqueous dispersion at various AYC concentrations were measured. AYC spray mists were optically observed. The surface of AYC cast film and AYC-coated granules were observed with a confocal scanning laser microscope. We attempted to show the utility of AYC as a novel material for granule coating, following the tablet coating in our previous report. In addition, the film formation mechanism of AYC was investigated. A smooth surface of the AYC-coated granules was obtained at a coating ratio of only 5%, which generally requires approximately 15-30% coating against the core granule weight, with no aggregation. These results are attributable to the fact that the granules were coated with a large number of small mists of AYC and the coating progressed efficiently, and the thin film layer of AYC was formed on the granules by mutual tangling of the hydrogel layers of AYC polysaccharides. AAP release from AYC-coated granules was obviously rapid, suggesting the high utility of AYC as a coating material for the rapidly releasing granules.

Clinical Experience with the Nikkiso Centrifugal Pump.

The Nikkiso HPM-15 is a minimally sized centrifugal pump. Preliminary results regarding clinical use of this pump for cardiopulmonary bypass (CPB) procedures have been reported previously. Recently, we have managed some additional cases using a newly developed controller. This article reports our clinical experiences with the use of this pump. We have managed 23 cases with a Nikkiso centrifugal pump. Twenty-two patients underwent CPB and 1 patient with fulminant viral myocarditis underwent percutaneous cardiopulmonary support (PCPS). With this pump, the circuit was extremely easy to prepare and deaeration was achieved readily. Hemodynamics during CPB and PCPS were stable in all cases. The increase in serum-free hemoglobin levels during CPB with this pump was as low as that seen in preliminary tests. A decrease in the platelet count was observed after the initiation of CPB with this pump; however, platelet counts returned to preoperative values 7 days after surgery. Moreover, urine output during CPB with this pump was as high as that seen in preliminary tests. No abnormalities in renal or liver function occurred during CPB. It appears that this new centrifugal pump is safe and easy to operate, and we conclude that it is useful for CPB and PCPS.