Kendal G. Pitt

An investigation into the physico-chemical properties of self-emulsifying systems using low frequency dielectric spectroscopy, surface tension measurements and particle size analysis

Abstract The structure and behaviour of self-emulsifying drug delivery systems (SEDDS) containing Labrafil M2125 CS and Tween 80 have been examined and the effects of changing the formulation via the addition of a non-polar model drug (L-365,260) investigated. Low frequency dielectric spectroscopy (LFDS) was used to examine the individual components in order to investigate the effects of drug inclusion. The presence of the drug resulted in a decrease in the dielectric response of the Labrafil M2125 CS, Tween 80 and the oil-surfactant vehicles. The surface tension of the emulsions decreased on addition of the drug, while particle size analysis showed that the emulsions containing no drug and 2% w/v drug had a bimodal distribution and the emulsions containing 6% w/v drug were unimodal. It was found that the bimodal distribution changed over a period of 14 h, with a decrease in modal value of the larger distribution peak and, for samples containing no drug, an increase in the proportion of droplets in the lower size distribution. The results therefore indicate that the drug interacts with one or more components of the self-emulsifying system, leading to a change in droplet size distribution which varies as a function of drug concentration.

Determination of baseline human nasal pH and the effect of intranasally administered buffers.

The nose is becoming a common route of drug administration, however, little is known about the pH of the human nasal cavity. Local pH may have a direct effect on the rate and extent of absorption of ionizable compounds and hence this study was performed to investigate normal pH values and whether pH could be manipulated by various buffers. Twelve healthy volunteers participated in a study to measure pH in the anterior and posterior sites of the nasal cavity. Miniature pH electrodes were placed 3 cm apart in the nasal cavity and a baseline was recorded for 30 min once the pH had stabilized. One hundred microlitres of isotonic solution was sprayed into the nostril and the pH was measured for 4 h post-dose. The following five formulations were tested: formulation A--sodium chloride (0.9%) at pH 7.2; formulation B--sodium chloride (0.9%) at pH 5.8; formulation C--Sorensens phosphate buffer (0.06 M) at pH 5. 8; formulation D--Sorensens phosphate buffer (0.13 M) at pH 5.8 and formulation E--formulation as (c) but adjusted to pH 5.0. Each formulation also contained saccharin sodium (0.5%) as a taste marker for nasal clearance. The time at which each subject detected the taste of saccharin was noted. The 30-minute baseline recording prior to administration of the nasal spray formulation demonstrates that there was both considerable intersubject and intrasubject variation in nasal pH. The average pH in the anterior of the nose was 6.40 (+0. 11, -0.15 S.D.) when calculated from H(+) values. The pH in the posterior of the nasal cavity was 6.27 (+0.13, -0.18 S.D.). The overall range in pH was 5.17-8.13 for anterior pH and 5.20-8.00 for posterior pH. Formulation A caused the pH in the anterior part of the nasal cavity to reach a maximum of 7.06 in 11.25 min from the baseline of pH 6.14 (P<0.05). The mean baseline pH was 6.5 for the posterior part of the nose which did not change over the recording period. Formulation B caused the anterior pH to increase from pH 6. 60 to 7.25 within the first minute. This fell back to a mean pH of 7.07 over the first hour which was still significantly above the baseline. It remained at this value for the remainder of the recording period. The initial average posterior pH was 6.32 and again this did not significantly change over the recording period. Formulation C produced a sustained increase in anterior nasal pH from a baseline pH of 6.57-7.12. A small transient decrease was observed in the pH in the posterior of the nose but baseline pH of 6. 6 was re-established within 15 min post dose. Formulation D significantly reduced anterior nasal pH from 6.30 to 5.87 by 30 min reaching a pH of 5.95 by 90 min where it remained for the remainder of the recording period. The posterior baseline pH was 6.3 and introduction of the pH 5.8 buffer caused a slow increase over 90 min to pH 6.6. Formulation E increased anterior pH from 6.1 to 6.7 for the remainder of the recording period. It had an insignificant effect on posterior nasal pH. The mean (+/-S.D.) time to taste saccharin for formulations A to E was 13.42+/-10.21, 14.67+/-8.37, 11.67+/-8.08, 10.08+/-7.6, 9.80+/-6.73 min, respectively. There was no significant difference between the clearance times for the different formulations. In conclusion, average baseline human nasal pH is approximately 6.3. Nasal anterior pH can be decreased when buffers of 0.13 M and above are used. Mildly acidic solutions produce an increase in pH presumably due to reflux bicarbonate secretion. Posterior nasal pH was not altered by administration of any buffer except the 0.13 M buffer at pH 5.8. This produced a rise in posterior pH.

Characterisation of the thermal properties of ethylcellulose using differential scanning and quasi-isothermal calorimetric approaches

The thermal behaviour of the ethylcellulose (EC), a polymer that is widely used in pharmaceutical dosage forms, has been investigated with a view to study the glass transition and higher temperature thermal events as well as to develop new approaches to characterise this complex polymer system. Samples of EC powder were studied using conventional and modulated temperature differential scanning calorimetry (MTDSC), quasi-isothermal (Qi-)MTDSC and hot stage microscopy (HSM) with simultaneous transmitted light intensity measurements. The T(g) was noted at circa 128-130 degrees C, with an accompanying baseline drift associated with a temperature dependent heat capacity change. A higher temperature combined endo/exothermic event was noted at 170-190 degrees C. TGA studies indicated that the exotherm was associated with oxidative degradation, with the accompanying DSC data being highly dependent on the sample encapsulation method used. The endotherm was found to be kinetically hindered, as demonstrated using Qi-MTDSC; the technique also indicated that there was little evidence for reversing processes through this transition. HSM studies indicated birefringence for the sample at low temperatures which disappeared as the material temperature approached T(g) but reappeared on further heating, again disappearing at circa 180 degrees C. Light intensity scans produced a profile similar to that seen for the DSC studies. It is proposed that the sample contains microcrystals composed of unsubstituted segments of the cellulose backbone. The implications of these findings for the understanding of the pharmaceutical behaviour and thermal characterisation of ethylcellulose are discussed.

New instrument for tribocharge measurement due to single particle impacts

During particulate solid processing, particle-particle and particle-wall collisions can generate electrostatic charges. This may lead to a variety of problems ranging from fire and explosion hazards to segregation, caking, and blocking. A fundamental understanding of the particle charging in such situations is therefore essential. For this purpose we have developed a new device that can measure charge transfer due to impact between a single particle and a metal plate. The device consists of an impact test system and two sets of Faraday cage and preamplifier for charge measurement. With current amplifiers, high-resolution measurements of particle charges of approximately 1 and 10 fC have been achieved before and after the impact, respectively. The device allows charge measurements of single particles with a size as small as approximately 100 microm impacting on the target at different incident angles with a velocity up to about 80 m/s. Further analyses of the charge transfer as a function of particle initial charge define an equilibrium charge, i.e., an initial charge level prior to impact for which no net charge transfer would occur as a result of impact.

Chapter 16 Tabletting

Publisher Summary Powder pressing is a forming process used in a wide range of industries, such as powder metallurgy, industrial ceramics, pharmaceutical tablets, food, detergents, fertilizers, batteries, magnets, and nuclear and hard metals. The process is fast, economic and lends itself to high-volume production. In spite of the broad range of powder materials and applications, powder pressing has common features in various industries. The operation consists of filling a die with powder, compressing using rigid punches, followed by ejection from the die. During this process, the loose powder bed is made compact according to a given shape and microstructure. Powder metallurgy compacts are required to have sufficient strength to withstand handling and have a dense, uniform, and defect-free microstructure. Compaction is followed by sintering to achieve near-full density and maximum strength for structural applications. The properties of a powder compact depend on the characteristics of the powder and the choice of process parameters during compaction. In order to achieve the desired compact properties the powders are mixed with other ingredients having specific functions. For example, lubricants are added to reduce the friction and wear of the tools and equipment. Steel powders may be mixed with graphite, which acts as a lubricant during compaction and alloying material can be mixed during sintering. Hard metal cutting tools are compressed by embedding the hard ceramic component into a soft metal matrix. In pharmaceutical tablets, the active ingredient is mixed with excipients such as lubricants (to control the friction between powder and tooling), glidants (to improve flow), binders (to improve strength), and disintegrants, which are polymers that swell in contact with water.

The effect of nasal patency on the clearance of radiolabeled saline in healthy volunteers

AbstractPurpose. The objective of this study was to investigate the effect ofnasal cavity patency on the penetration, deposition, and clearance ofan aqueous isotonic saline solution. Methods. The study was carried out as a single center, open,randomized, 2-way cross-over in healthy volunteers. Nasal patency wasassessed using misting patterns on a cold metal surface at the beginningand end of study. 100 μl of technetium-99m radiolabeled saline solutionwas introduced into either the most or least patent nasal cavity usinga purpose designed spray device. The distribution and residence timeof the radiolabel was followed for 2 hours using gamma scintigraphy. Results. The mean times to 50% clearance were34 ± 7 and 28 ± 12minutes (±s.d.) for the side view of the least and most patent nasalcavity respectively. Total clearance of the radiolabelled saline from thenose was not affected by patency. Between 7 and 3% of theradiolabelled saline solution remained in the nasal cavity at the end of imaging.Using endoscopy to track the clearance of an aqueous solution of fooddye using the same delivery procedure, identified this region as hairin the nasal vestibule. The dye was seen to dry in this region alongwith the mucus. Conclusions. Nasal patency affects the initial, but not total clearanceof solutions, however, the remaining solution may not be available fordrug delivery.

Chapter 22 The strength of pharmaceutical tablets

Publisher Summary This chapter discusses issues related to pharmaceutical tablet strength. The strength of flat and curved-faced tablets and other characterization methods, such as bending tests are presented in the chapter. Tablets are produced by die compaction, which consists of filling a die with powder, compression between two rigid punches and ejection from the die. The strength of the tablets is dependent on the state of densification of the powder, which is given by the applied force. The resulting tablet is subject to bulk handling and other post-compaction operations during which it must maintain mechanical integrity. In industrial practice, the most commonly applied strength measurement for a compact is the diametrical compression test. The test is simple and easy to perform and has been widely used to determine the tensile strength of a variety of brittle materials such as concrete, coal briquettes, gypsum, and lactose tablets. The mechanical and bioavailability properties of tablets are dependent not only on the composition of the powder blend but also on the process parameters during compaction, which are also defined in the chapter.