Visualization and prediction of porosity in roller compacted ribbons with near-infrared chemical imaging (NIR-CI).

The porosity of roller compacted ribbon is recognized as an important critical quality attribute which has a huge impact on the final product quality. The purpose of this study was to investigate the use of near-infrared chemical imaging (NIR-CI) for porosity estimation of ribbons produced at different roll pressures. Two off-line methods were utilized as reference methods. The relatively fast method (oil absorption) was comparable with the more time-consuming mercury intrusion method (R(2)=0.98). Therefore, the oil method was selected as the reference off line method. It was confirmed by both reference methods that ribbons compressed at a higher pressure resulted in a lower mean porosity. Using NIR-CI in combination with multivariate data analysis it was possible to visualize and predict the porosity distribution of the ribbons. This approach is considered important for process monitoring and control of continuously operating roller compaction line.

Compressibility and compactibility of granules produced by wet and dry granulation.

The bulk properties, compactibility and compressibility of granules produced by wet and dry granulation were compared applying a rotary tablet press, three different morphological forms of calcium carbonate and two particle sizes of sorbitol. Granules from both granulation methods possessed acceptable flow properties; however, the ground (Mikhart) and cubic (Scoralite) calcium carbonate demonstrated better die-filling abilities in the tablet press than the scalenhedral calcium carbonate (Sturcal). The wet processed granules showed in general larger compression properties. This was explained as these granules were mechanical stronger and had a higher initial porosity. In some cases, a large particle surface area of calcium carbonate and sorbitol resulted in a small, insignificant improvement of the consolidation characteristics. A correlation between the compression and compaction characteristics was demonstrated.

Granule fraction inhomogeneity of calcium carbonate/sorbitol in roller compacted granules.

The granule fraction inhomogeneity of roller compacted granules was examined on mixtures of three different morphologic forms of calcium carbonate and three particle sizes of sorbitol. The granule fraction inhomogeneity was determined by the distribution of the calcium carbonate in each of the 10 size fractions between 0 and 2000 microm and by calculating the demixing potential. Significant inhomogeneous occurrence of calcium carbonate in the size fractions was demonstrated, depending mostly on the particles sizes of sorbitol but also on the morphological forms of calcium carbonate. The heterogeneous distribution of calcium carbonate was related to the decrease in compactibility of roller compacted granules in comparison to the ungranulated materials. This phenomenon was explained by a mechanism where fracturing of the ribbon during granulation occurred at the weakest interparticulate bonds (the calcium carbonate: calcium carbonate bonds) and consequently exposed the weakest areas of bond formation on the surface of the granules. Accordingly, the non-uniform allocation of the interparticulate attractive forces in a tablet would cause a lowering of the compactibility. Furthermore, the ability of the powder to agglomerate in the roller compactor was demonstrated to be related to the ability of the powder to be compacted into a tablet, thus the most compactable calcium carbonate and the smallest sized sorbitol improved the homogeneity by decreasing the demixing potential.

Improving the compaction properties of roller compacted calcium carbonate.

The effects of roller compaction process parameters, morphological forms of calcium carbonate and particle size of sorbitol on flow, compaction and compression properties were investigated. The morphology of the calcium carbonate and the sorbitol particle size were more influential on the compaction properties than the settings of the roller compactor. The roller compaction process was demonstrated to be robust and stable in regard to flowability and compactibility. The flowability of the granules was improved adequately to facilitate compression in a production scale rotary tablet press. By adding sorbitol to the calcium carbonate, the compressibility - characterized by the Walker coefficient W(ID) - and the compactibility C(P) were improved considerably. A correlation between the consolidation characteristics was demonstrated. Compactibility data from the compaction simulator correlated with the tablet press for two of the calcium carbonates, the cubic form and the ground quality.

Optimization of self-microemulsifying drug delivery systems (SMEDDS) using a D-optimal design and the desirability function.

D-optimal design and the desirability function were applied to optimize a self-microemulsifying drug delivery system (SMEDDS). The optimized key parameters were the following: 1) particle size of the dispersed emulsion, 2) solubility of the drug in the vehicle, and 3) the vehicle compatibility with the hard gelatin capsule. Three formulation variables, PEG200, a surfactant mixture, and an oil mixture, were included in the experimental design. The results of the mathematical analysis of the data demonstrated significant interactions among the formulation variables, and the desirability function was demonstrated to be a powerful tool to predict the optimal formulation for the explored system.

On the misinterpretation of the correlation coefficient in pharmaceutical sciences.

The correlation coefficient is often used and more often misused as a universal parameter expressing the quality in linear regression analysis. The popularity of this dimensionless quantity is evident as it is easy to communicate and considered to be unproblematic to comprehend. However, illustrative examples will demonstrate that the correlation coefficient is highly ineffective as a stand-alone quantity without reference to the number of observations, the pattern of the data and the slope of the regression line. Much more efficient quality methodologies are available where the correct technique depends on the purpose of the investigation. These relevant and precise methods in quality assurance of linear regression as alternative to the correlation coefficient are presented.

Patients' evaluation of shape, size and colour of solid dosage forms.

AIM: The aim of the study was to investigate the swallow ability and the patient preferences of tablets and capsules with different sizes, shapes, surfaces and colours. METHOD: Patients were asked to swallow tablets with different surface and size, while tablets with different shape and colour were visually assessed. They were asked to indicate their preferences. RESULTS: Gelatine capsules were found easier to swallow than tablets and coated tablets were found easier than uncoated normal tablets. The preferred colour was white both for tables and capsules, and the most disliked colours were purple tablets and brown capsules. The preferred shape was strongly arched circular for small tablets, oval for medium sized and big tablets. The difficulty to swallow tablets increased with increasing size. CONCLUSION: According to the results of this study, the ideal tablet is small and white, strongly arched circular and coated. If the amount of drug requires a bigger tablet, the preferred fomat is oblong or oval with a coating. In general capsules were preferred over tablets.

Investigation of a new mathematical model for compression of pharmaceutical powders.

A new compaction equation, the log-exp model: V=V(l)-w log(P)+V(e) exp(P/P(m)) is presented. The model presumes that two compaction processes: a logarithmic and an exponential decline may be active simultaneously. Using non-linear regression techniques the model gives an excellent fit to a number of model substances with wide differences in compaction behaviour. Compared to the Kawakita equation the model covers a broader range of the compaction profile. The new model and the Cooper and Eaton equation fit the data on the same level, but the parameters derived from the log-exp model seems to have more discriminative power between substances and have a close relation to the apparent plastic or brittle densification mechanism. The log-exp model has potential as a tool in estimation of the strength of agglomerated materials. A proposal for a set-up to an iterative non-linear regression calculation in a spreadsheet program is attached.

Impact of particle density and initial volume on mathematical compression models.

In the calculation of the coefficients of compression models for powders either the initial volume or the particle density is introduced as a normalising factor. The influence of these normalising factors is, however, widely different on coefficients derived from the Kawakita, Walker and Heckel equations. The problems are illustrated by investigations on compaction profiles of 17 materials with different molecular structures and particle densities. It is shown that the particle density of materials with covalent bonds in the Heckel model acts as a key parameter with a dominating influence on the derived apparent yield pressures. Substances with ionic bonds or macromolecular materials with amorphous structures do not show this dependency on the particle density. The influence of density is demonstrated by performing non-linear regression on the Heckel equation where the optimal particle density is estimated. The a parameter in the Kawakita equation is not influenced to a greater degree by variation in the initial volume.

A critical evaluation of the Heckel equation.

Great differences between published Heckel parameters, obtained from 'at pressure' data or the 'in-die' method, are outlined. The general validity of the concept of yield pressures derived from slopes of such Heckel plots is questioned. When the ability of the Heckel and the Walker equations is compared to fit density/pressure data from tabletting different pharmaceutical powders, a generally better fit is obtained with the Walker equation in the region of 5-100 MPa. The ability to discriminate between materials by data from the compression phase is improved by using the Walker model. For Emcompress(R), apparent yield pressures derived from Heckel plots are dependent strongly on the maximum pressure of the compression process.

[Postoperative pain in children. A comparison between ratings of children and nurses]. / Postoperative smerter hos børn. Sammenligning mellem børnenes og sygeplejerskernes vurderinger.

Several predominantly North American studies indicate that postoperative pain experienced by children is underestimated by the nurses, who are in charge of the analgesic treatment of the children's pain. The purpose of this investigation was to examine, in Danish children, the relationship between the children's ratings of their pain and the nurses' ratings of the children's pain. The issue was examined by comparing the pain ratings of 100 children three to 15 years of age following tonsillectomy. The ratings were obtained by using the Poker Chip Tool and a 10-cm Visual analogue scale. The differences between the children's and the nurses' pain ratings were most pronounced after administration of analgesics (p < 0.001). After analgesics, the children's mean pain score was 17% lower than before analgesics, while the nurses' mean pain scores of the children's pain were 53-58% lower than before analgesics. Consistent with results from foreign studies, this Danish study found that, in general, the nurses underestimated the children's pain. The nurses tended to overestimate the effect of analgesics and tended to modify their pain ratings according to the children's level of activity.

Pain assessment of subcutaneous injections.

OBJECTIVE: To compare injection pain after subcutaneous administration of four different solution volumes. DESIGN: Double-blind, randomized, prospective, multiple crossover study. SETTING: Steno Diabetes Center, Gentofte, Denmark. PARTICIPANTS: Eighteen healthy volunteers, 9 women and 9 men, aged 21-30 years. METHODS: The subjects were injected with four different volumes (0.2, 0.5, 1.0, 1.5 mL) of NaCl 0.9%. The study was performed on 2 days with a 1-week washout period between the study days. On each study day the subjects received four injections in each thigh. To evaluate the validity of our pain assessing model the subjects received eight injections of 0.5% mL on one of the study days. Pain assessment was done immediately after each injection using both a 10-cm visual analog scale (VAS) and a six-item verbal rating scale (VRS). RESULTS: A significant difference in pain score on both the VAS (p < 0.05) and the VRS (p < 0.01) was seen between the four injection volumes. The pain was significantly increased with volumes of 1.0 and 1.5 mL. No significant difference in injection pain could be detected between 0.2 and 0.5 mL and between 1.0 and 1.5 mL. No significant period or carryover effect could be detected in the study. A significant correlation between the pain score on the VAS and the pain score on the VRS was found (r = 0.79, p < 0.0001). CONCLUSIONS: The pain of a subcutaneous injection is related to injection volume in the thigh. The results show that increasing the volume from 0.5 to 1.0 mL increases the pain significantly. The findings from this study should be considered when injection preparations for subcutaneous administration are formulated. The volume should generally be less than 1.0 mL if injected into the thigh.

Bioavailability of the antiemetic metopimazine given as a microenema.

The absorption of the antiemetic metopimazine (MPZ) given as a single dose of (a) 40 mg microenema, (b) 40 mg orally and (c) 10 mg as a 60 min i.v. continuous infusion was investigated in six healthy volunteers. Blood samples were drawn and the serum concentrations of MPZ and its acid metabolite were measured. The bioavailability of MPZ given orally and as enemas was 22.3 and 19.5% respectively. Partial avoidance of hepatic first pass metabolism was seen with the enemas, which in contrast to suppositories, seems to represent a reliable form of rectal administration.

Postoperative pain in Danish children: self-report measures of pain intensity.

The Oucher and the Poker Chip Tool are two of the most widely used instruments designed to measure children's self-report of pain intensity. Most of the studies dealing with the Oucher and the Poker Chip Tool use North American children as subjects. To establish the versatility of the instruments in patients of various cultural backgrounds and with different types of pain, this study used the Oucher and the Poker Chip Tool with 100 Danish children, age 3 to 15 years, after tonsillectomy. Both the Oucher and the Poker Chip Tool provided easy-to-use devices in clinical practice for the estimation of the intensity of the children's pain. Although the Poker Chip Tool only provides five discrete levels of pain, the strong positive relationships between the pain scores derived from the Oucher and the Poker Chip Tool (r = 0.71-0.79, p < .001) indicate its utility in clinical practice. The Oucher uses actual pictures of a child and therefore demonstrates ethnicity directly. The results of this study suggest that Danish children as well as American children are able to use the Oucher as a method to self-report pain intensity.

Postoperative pain in children: comparison between ratings of children and nurses.

Frequently, decisions about analgesic treatment of postoperative pain in children are based on judgments made by nurses. Several studies from North America indicate that nurses underestimate the amount of pain experienced by children. Additional investigations are required to evaluate the extent to which this problem affects children in other countries and societies that have various health-care systems. The purpose of this study was to examine the relationship between children's ratings of their pain and the nurses' ratings of the children's pain in a Danish hospital. The issue was examined by comparing the pain ratings of 100 children 3-15 years of age following tonsillectomy. The ratings were obtained by using the poker chip tool and a 10-cm visual analogue scale. In general, nurses underestimated the children's pain. The differences were most pronounced after analgesics (P < 0.001). The nurses tended to overestimate the effect of analgesics. Although the correlations between the children's and the nurses' pain scores were statistically significant (r = 0.35-0.43, P < 0.001), the findings indicate that the nurses are not good at interpreting the patients' pain. These results from Danish children and nurses are similar to studies in other populations.

Bioavailability of four oral coenzyme Q10 formulations in healthy volunteers.

The bioavailability of four different Coenzyme Q10 (CoQ) formulations was compared in ten healthy volunteers in a four-way randomised cross-over trial. The included formulations were: A hard gelatin capsule containing 100 mg of CoQ and 400 mg of Emcompress. Three soft gelatin capsules containing: 100 mg of CoQ with 400 mg of soy bean oil (Bioquinon); 100 mg of CoQ with 20 mg of polysorbate 80, 100 mg of lecithin and 280 mg of soy bean oil; and 100 mg of CoQ with 20 mg of polysorbate 80 and 380 mg of soy bean oil, respectively. The result suggests that the soya bean oil suspension of CoQ (Bioquinon has the highest bioavailability. A difference in basic AUC and AUC after p.o. administration of CoQ was observed with respect to sex. A characteristic two peak-pattern was observed at the concentration-time profile.

Single-dose and steady-state pharmacokinetics of diltiazem administered in two different tablet formulations.

Single-dose and steady state pharmacokinetics of diltiazem administered in two different oral formulations were assessed with particular reference to rate and extent of absorption. Following single dose administration a significant difference in tmax was observed (2.9 +/- 1.9 and 6.8 +/- 2.6 hr respectively) whereas differences in AUC, t1/2 and Cmax were not significant. The AUC (mean +/- S.D.) values following single dose administration of Cardil and Cardizem were 678.4 +/- 321.5 and 948.6 +/- 580.6 ng.ml-1.hr respectively. The mean and the 95% confidence limits for the observed ratio AUCCardil/AUCCardizem are 0.89 and 0.44-1.34 respectively. At steady-state a significant difference between Cmax/Cmin and tmax was seen Cmax/Cmin being 4.9 and 3.2 respectively and Tmax being 2.7 +/- 2.0 and 6.0 +/- 2.8 hr respectively, whereas Cmax and AUC did not differ significantly. The AUC (mean +/- S.D.) values in steady state of Cardil and Cardizem were 880.1 +/- 399.8 and 1056.8 +/- 509.8 ng.ml-1.hr respectively. The mean and the 95% confidence limits for the observed ratio AUCCardil/AUCCardizem are 0.96 and 0.66-1.26 respectively. Although the observed ratios AUCCardil/AUCCardizem in both the single-dose and the steady-state study do not differ significantly from 1.0, the confidence limits exceed the acceptable values given by Poulsen & Juul (personal communication 1990) (a 20% decrease or increase of the ratio to 0.8 or 1.2).