A review of the science presentations
Joe Chamberlain, science secretary for the British Pharmaceutical Conference from 1990 to 1999 and a former editor of The Journal of Pharmacy and Pharmacology, highlights a selection of the work that will be reported in the science sessions at BPC
2004 next week
The theme of this year’s British Pharmaceutical Conference is “Medicines:
from cell to society” and the range of subject matter in the short
science papers presented will underline the role of pharmaceutical scientists
in this process.
More than 200 short papers will be presented this year. Apart from sessions
for short papers in pharmaceutical analysis and pharmacognosy, jointly
organised by the Joint Pharmaceutical Analysis Group, all submitted papers
will be presented as posters. However, selected posters will also be
presented in special discussion sessions.
The following review groups highlighted papers according to similar research
topics. The full abstracts can be downloaded from the BPC
section of
the Royal Pharmaceutical Society’s website.
Pharmaceutics: materials
Li et al (Welsh School of Pharmacy, Aston University and Royal Gwent
Hospital, Newport) describe spray-drying as an effective and convenient
method of producing appropriately sized respirable particles. Using
salbutamol sulphate as a model drug they show that trehalose-based
spray-dried powders offer an improvement over lactose-based powders,
and that the inclusion of leucine into the formulation before spray-drying
can enhance the respirable fraction of the spray-dried powder.
Sharma-Singh and Kirk (AstraZeneca) report on the progress made in
assessing the feasibility of applying in situ fibre optics to assess
the intrinsic
dissolution rate of active pharmaceutical ingredients. Their results
indicate similar results to off-line high performance luqiud chromatography
analysis and suggest fibre optics could be routinely applied, enabling
considerable time and cost savings.
Drugs formulated in hyaluronan, a naturally occurring polyanionic glycosaminoglycan,
and applied topically are retained in the skin with little systemic absorption.
He et al (King’s College London) investigate this mechanism of
action of hyaluronan by studying the effect of different molecular weight
hyaluronans on diclofenac and ibuprofen. Their work suggests that hyaluronan
might affect drug release from the vehicle due to the altered solubility
or diffusivity of active drug in the hyaluronan vehicles. Drug design
based on receptor targeting tends to recommend lipophilic compounds,
in which dissolution characteristics are compromised. This situation
has driven the development of strategies to maximise bioavailability
by influencing the dissolution process of such compounds.
Rawlinson et al (University of Bradford and
Bristol Myers-Squibb) report on studies investigating the formation of
an amorphous species of ibuprofen
upon combination with cross-linked poly-vinyl-pyrrolidone using simple
mixing to facilitate intimate contact. The stabilisation of the amorphous
drug species, caused by the partial disordering of ibuprofen, should
improve its dissolution characteristics.
Concerns over BSE and vCJD have led Burke et
al to investigate whether
gelatin derived from fish can replace mammalian gelatin in pharmaceutical
applications |
Recent concerns over the spread
of bovine spongiform encephalopathy and variant Creutzfeldt-Jakob disease,
along with a trend to vegetarianism,
have led to a search for alternatives to mammalian gelatin for pharmaceutical
use. Burke et al (Liverpool John Moores University)
evaluate the thermal and mechanical properties of a range of softgel
ribbons, based on bovine,
porcine and fish gelatin. Bovine and porcine gelatin behaved similarly
but fish gelatin yielded a more elastic ribbon. These differences may
relate to differences in the structure and composition of the gelatin,
and suggest fish gelatin may be a useful replacement for mammalian
gelatin in the manufacture of pharmaceutical softgel capsules.
Pharmaceutics: liposomes and niosomes
The solubility and partitioning behaviour of a drug molecule governs
its location in the liposome structure; highly hydrophilic drugs (logP<1.7)
are located exclusively in the aqueous compartment of the liposomes
while lipophilic drugs (logP >5) are entrapped in the lipid bilayer.
Mohammed et al (Aston University and Pfizer UK) enhance the solubility
of problematic drugs (logP between 2 and 4) by exploiting the physicochemical
properties of liposomal systems. Incorporation studies demonstrated
drug loading could be enhanced by increasing the liposomal hydrophobic
volume although the extent of this enhanced drug loading was strongly
dictated by the logP of the drug. Thus both the physicochemical properties
of the drug molecules and the lipid bilayer composition must be considered
collectively when designing liposome-based solubilisation systems.
Vangala and Perrie (Aston University) evaluate the physicochemical
characteristics of DNA-loaded dehydration-rehydration vesicle niosomes
in the presence
of sucrose and trehalose as cryoprotectants. The disaccharides could
efficiently be employed without significantly influencing encapsulation
efficiency; a pronounced effect was observed on vesicle size yielding
submicron sizes, which could further be lowered by increasing surfactant
hydrophobicity and thereby reducing the overall surface free energy.
Pharmaceutics: particles
Whitaker et al (Critical Pharmaceuticals Ltd and University of Nottingham)
address the outstanding problems of formulating proteins in a microparticle
system, particularly the problem of heat denaturation of the protein
during polymer mobilisation. Supercritical carbon dioxide was used
as a processing medium for the fabrication of poly(dl-lactic acid)
microparticles that encapsulate a protein material where the processing
can be performed at 35C and in the complete absence of conventional
organic solvents.
As part of an investigation into understanding the nature of the interaction
between stabilising polymers and drug nanoparticles, Goodwin
et al (King’s
College London and GlaxoSmithKline) studied the effect of polymer molecular
weight on size reduction. More than four hours of wet-milling was required
to obtain nabumetone particles in the submicron size range using undegraded
hydroxypropylcellulose. However, nanoparticles were formed after less
than two hours using hydroxypropylcellulose which had had been exposed
to ultrasonic degradation. This more rapid reduction in drug particle
size could be explained by a greater milling efficiency due to a lower
viscosity or by lower molecular weight polymers having a faster ability
to diffuse to the newly generated drug particle surfaces.
Biopharmaceutics: microbiological issues
Keegan et al (University of Brighton, University of Portsmouth and
GlaxoSmithKline Research & Development) aim to develop zinc/polycarboxylate complexes
that are retained within the oral cavity to provide sustained antimicrobial
protection against oral pathogens. An association forms between the
polycarboxylate and zinc ions, and the presence of sodium and calcium
ions in saliva will allow displacement of the zinc. Thus these complexes
have the potential to form a bio-responsive antimicrobial delivery
system that will preferentially release the antimicrobial agent in
lower pH environments, such as those generated in the oral cavity by
cariogenic microorganisms.
The difficulty in eradicating established microbial biofilm using parenteral
antibiotics has led to the assessment of nebulised gentamicin as a preventive
strategy for ventilator-associated pneumonia. In an effort to enhance
the attachment of gentamicin to the surface of the endotracheal tube,
McCrory et al (Queen’s University of Belfast) describe a macroporous
hydrogel system loaded with gentamicin to coat the tube to reduce bacterial
colonisation. A greater gentamicin loading was obtained with drug incorporated
before polymerisation as opposed to soaking the hydrogels in a buffered
gentamicin solution after polymerisation.
Similarly, McBride et al (Queen’s University of Belfast) have studied
the adherence and persistence of activity of antimicrobial-incorporated
teraoctyldodecoxysilane silicones. The antimicrobial-incorporated elastomers
showed significantly lower adherence and a significantly longer persistence
of activity, compared with the control silicone. The incorporation of
the antimicrobials did not significantly affect the tensile strength
or the contact angle of the silicone. The coefficient of friction of
the novel material was significantly lower than the control silicone,
due to the production and release of the oily alcohol, octyldodecanol.
There are potential benefits of the antimicrobial-incorporated teraoctyldodecoxysilane
silicones over existing silicones through the production of this renewable
lubricious surface.
Biopharmaceutics: drug metabolism
Siddique et al (University of Strathclyde, University of Glasgow and
AstraZeneca) describe the use of amphiphilic conjugates of doxorubicin
in a programme to alleviate the side effects of such drugs, by modifying
drug pharmacokinetics and biodistribution. The conjugates initially
accumulate in the cell membrane and within small spherical compartments
within the cell indicating endocytosis, potentially bypassing the P-glycoprotein
pump. The conjugates were similar in cytotoxicity and showed an increase
in dose tolerance in comparison with doxorubicin.
Carlsson et al (AstraZeneca R&D and Uppsala University, Sweden) verify
enzyme-mediated degradation in intestinal fluid of a model drug and compare
the degradation in human intestinal fluid and dog intestinal fluid. The
parent drug, an ester, and the expected degradation product, the corresponding
acid, are determined by HPLC. Enzyme-mediated degradation in the intestine
can be determined by in vitro testing in real intestinal fluids, and
should thus be a useful tool in early drug development. The dog seems
to be a reasonably good model for man, although the degradation capacity
seems to be somewhat higher possibly due to a higher enzyme concentration.
Drug delivery: adhesion
Mortazavi (Shaheed Beheshti University of Medical Sciences, Iran) investigates
the influence of wet granulation on the mucoadhesive properties of
tablets prepared from cellulose derivatives. Tablets prepared by
completely granulating cellulose mixtures had lower mucoadhesive strengths
than
their corresponding formulations which were partially granulated.
However, the duration of mucoadhesion of tablets was found to improve
by granulation.
Increasing the concentration of extra-granular sodium carboxymethylcellulose
helped to increase the mucoadhesive strength of the resulting tablets,
although the duration of mucoadhesion of the test tablet was reduced.
In contrast, increasing the amount of hydroxypropylmethylcellulose
in the tablet, and in particular within the granules, resulted in
an increased duration of mucoadhesion, despite lowering the mucoadhesive
strength of the formulation.
Russell et al (Aston University) extend their previous work on the
adhesion of polyacrylic acids to the oesophagus by studying the potential
of the
polyacrylic acid Noveon AA1 for efficient delivery of isosorbide dinitrate
and nifedipine as model drugs. They compare the in vitro oesophageal
retention of Noveon AA1 and simple emulsions and measure the rate of
drug release from these formulations. Drug release for isosorbide dinitrate
is significantly greater than that for nifedipine from all formulations.
For both drugs, drug release from Noveon AA1 is related to viscosity,
with significantly improved release from the lower viscosity pH 4.7
solution. At high concentrations, isosorbide dinitrate is released
more rapidly
from light mineral oil emulsion compared with heavy mineral oil emulsion,
yet the reverse is true for nifedipine. Both Noveon AA1 and the emulsions
tested demonstrate potential for bioadhesion to the oesophagus in vitro.
Drugs are successfully released within a short time and the systems
have potential for oesophageal delivery.
Suresh et al (Al-Ameen College of Pharmacy, Bangalore, India, and University
of East Anglia) investigate the use of alginate microparticles as a
sustained delivery system for oesophageal delivery. The retention of
alginate microparticles
on the oesophageal tissue is significantly higher than that of an equivalent
alginate solution. For both formulations, the greatest loss is observed
in the first 20 minutes, although the solution continues to show greater
loss thereafter. It may be possible to develop an alginate microparticulate
formulation that is retained on the surface of the oesophagus for prolonged
periods, thus enabling the incorporated or attached drug to be adsorbed
onto or absorbed into the oesophageal tissue.
Drug delivery: oral delivery
The mechanism by which oil-free polyethylenimine formulations promote
the oral absorption of the hydrophobic immune suppressant ciclosporin
is currently unknown. Cheng and Uchegbu (University of Strathclyde)
set out to examine whether the inhibition of the intestinal P-glycoprotein
efflux pump or the opening of paracellular transport pathways is involved
in the absorption enhancement observed with these solubilising polyethylenimine
amphiphiles. They find that increasing the number of amine groups increases
the cytotoxicity of the polyamines and that amine substitution reduces
the cytotoxicity of the long chain polyamines. However, at biocompatible
concentrations, the polyethylenimine amphiphiles do not act by either
a modulation of the P-glycoprotein pump or by altering the paracellular
junctions.
The design, synthesis and characterisation of a series of dendrimer-based
prodrugs for the enhancement of drug solubility and permeability are
described by Najlah et al (University of Manchester). Naproxen is selected
as a model low-solubility drug and conjugated to dendrimers by an amide
bond or an ester bond. The results indicate a high chemical and enzymatic
stability of the amide-linked conjugate with slow release of the parent
drug in human plasma making these conjugates suitable for further study
as prodrugs.
From the same group, Jevprasesphant et al (University of Manchester)
investigate the transport mechanisms of dendrimers and surface-modified
dendrimer conjugates across Caco-2 cell monolayers, and also the use
of dendrimer–drug conjugates to enhance the solubility of poorly
soluble drugs and bypass the P-glycoprotein efflux transporter. Dendrimer
and lauroyl-dendrimer conjugates were chemically bound to propranolol
base, a model P-glycoprotein substrate and low-solubility drug. The results
suggest that dendrimer carriers bypass the P-glycoprotein efflux transporter
by a method involving endocytosis. No difference in the permeability
of propranolol–dendrimer conjugates is apparent in the presence
and absence of ciclosporin A, indicating that the conjugates are not
P-glycoprotein substrates.
Drug delivery: other routes
Jahan et al (School of Pharmacy, University of London) extend previous
work on the in vivo electroresponsive release of a model drug diclofenac
in rats, from chitosan hydrogels. Diclofenac could be released from
chitosan hydrogel in a pulsatile fashion in response to repeated pulses
of electrical stimuli. Some release of drug during the “off” period
is also observed, probably due to drug diffusion along a concentration
gradient. The electro-stimulated release may be attributed to syneresis
of the gel, with concomitant drug expulsion or to electrophoresis of
the negatively charged drug towards the anode.
In a separate paper, the same group describe electro-responsive release
of diclofenac from chitosan microspheres. A burst release of drug is
observed, after which diclofenac levels rise slowly in both electro-stimulated
and control rats, although the burst release and the subsequent gradual
drug release are greater in rats that have been electrostimulated; enhanced
drug release is probably via electrophoresis of the drug towards the
anode. This is the first report of electro-responsive drug release from
gel microspheres in vivo.
Donnelly et al (Queen’s University of Belfast) note that the zwitterionic
nature of aminolevulinic acid, widely used in topical photodynamic therapy,
impairs drug penetration, being ionised at both high and low pH. Topically
applied aminolevulinic acid, therefore, penetrates intact stratum corneum
poorly. Bioadhesive patches containing 14C-labelled aminolevulinic acid
are prepared containing 0–5 per cent of either dimethyl sulphoxide
or oleic acid. Patch segments are applied to equal areas of neonate porcine
skin and allowed to remain in place for four hours at 37C. Sectioned
skin samples are assessed by liquid scintillation spectroscopy. Neither
dimethyl sulphoxide nor oleic acid have significantly useful influences
on aminolevulinic acid concentration at a depth of 2.375mm.
Ammar et al (Cairo University) present a comprehensive study on the development
of a transdermal delivery system for glipizide which would circumvent
the problems associated with oral therapy of the antidiabetic. They prepared
inclusion complexes of the drug in a range of beta-cyclodextrins and
developed several percutaneous formulations for the drug and the prepared
complexes in different bases. The results reveal sustained effect of
the drug for about 48 hours, as well as suppression of hypoglycaemia
induced in glucose-loaded rats. The best biological performance was shown
by a glipizide-dimethyl-beta-cyclodextrin complex in Carbopol gel base
in the presence of urea and by glipizide in the same base in the presence
of propylene glycol together with oleic acid.
Drug delivery: gene delivery
Microneedle arrays are a novel intra/transdermal delivery device that
provides access to the viable cells of the epidermis through the creation
of microchannels within the stratum corneum. Coulman et al (Cardiff
University and Royal Gwent Hospital) aim to combine the cutaneous delivery
potential of a microneedle device with the rational design of non-viral
gene therapy formulations to create a controllable therapeutic gene
delivery system. The visualisation of microconduits within the stratum
corneum, approximately 15µm in diameter, is followed by the microneedle-mediated
delivery of fluorescent colloidal nanoparticles to the viable cells
within the human epidermis. These studies confirm the capability of
a microneedle array to create a route of delivery for macromolecular
gene therapy formulations.
Omidi et al (Welsh School of Pharmacy, Tabriz University of Medical
Sciences, Iran and University of Setif, Algeria) assess the toxicogenomics
of starburst
polyamidoamine dendrimers and polypropylenimine diaminobutane dendrimers
and demonstrate that these dendrimeric delivery systems for gene therapy
intrinsically alter gene expression in human epithelial cells. The nature
of the genes whose expression is induced by these dendrimeric nanostructures
is diverse and includes some common genes, among which are those related
to apoptosis and stress as well as membrane receptors and transcription
factors. Thus, certain dendrimers can induce diverse gene expression
changes in cells and cannot truly be considered to be genocompatible.
Lam et al (University of Nottingham, University of Sussex and Biocompatibles
International) describe a novel diblock copolymer as a potential vector
for gene delivery. Evaluation of the diblock copolymer showed that the
presence of a methacryloyloxyethyl phosphorylcholine block prevents aggregation
of the DNA condensates by providing steric stabilisation, creating condensates
with sub-200nm average diameter. However, the steric stabilisation effect
of the block has to be balanced against the decreased ability of the
copolymers to provide efficient DNA condensation as the length of the
methacryloyloxyethyl phosphorylcholine moiety increases. The reduced
level of DNA condensation is directly related to the decreased level
of DNA protection from enzymatic degradation in vitro. Careful design
of the copolymer architecture is required to balance the stabilising
and DNA condensing properties of the copolymers.
Barlow et al (King’s College London and Laue Langevin Institute,
Grenoble) aim to establish the existence and extent of the interactions
of calcium with zwitterions using neutron reflectivity, examining the
effects of DNA, in the presence and absence of calcium, on a monolayer
formed at the air-water interface by the zwitterionic phospholipid 1,2-distearoyl-sn-glycero-3-phosphocholine.
Structural changes to the phospholipid monolayer are observed in the
presence of calcium that are a direct result of interaction with DNA.
Although the thickness of the lipid hydrocarbon layer remains constant
(at ~25Å) after the addition of DNA, there is a marked decrease
in the scattering length density of the adsorbed layer. This indicates
insertion of hydrogenous material into the layer, or a structural rearrangement
of the molecules within the layer to occupy a greater interfacial area.
Changes of a similar nature are observed in the absence of calcium but
occur much more slowly and are of a much smaller magnitude. Thus calcium
promotes interactions between zwitterionic phospholipids and DNA, and
these systems might make suitable (non-toxic) vectors for gene delivery.
Pharmacognosy: analysis
Herbal medicine is gaining interest because of supposed reduced side
effects, but safety and efficacy data are limited. Langyan
and Ahuja (Hisar University, India) study the accumulation of nickel and cobalt
in some Indian herbal preparations (churna, guggulu, bati, ras, pishti
and arishtas). Eleven marketed products show varying amounts of nickel
and cobalt. These metal ions may have entered through the raw material
or during processing. Some herbal remedies do contain metal ions
as their therapeutically active ingredients but the authors suggest they
should not be considered as dietary supplements for these compounds.
Putalun et al (Khon Kaen University, Thailand, and Kyushu University,
Japan) seek a rapid determination method for glycyrrhizin, suitable
for use in plant samples and report the development of a rapid immunochromatographic
assay for the detection of glycyrrhizin. This qualitative assay is
based
on a competitive immunoassay in which the detector reagent consists
of colloidal gold particles coated with anti-glycyrrhizin monoclonal
antibodies.
The detection limit for the strip test is 250ng/ml. The appropriate
sample volume size was 200ml, and the assay can be performed in about
10 minutes.
The immunochromatographic strip assay is suitable as a rapid and simple
procedure for screening glycyrrhizin concentrations in plants, biological
fluid and food samples.
Reid et al (Robert Gordon University, Aberdeen) report the separation
and quantification of the main alkaloids found in opium samples and
poppy straw using capillary electrophoresis, an improvement on previous
chromatographic
methods. Distinct profiles of different opium samples (Persian, Indian,
Turkish and Yugoslavian), along with those for different poppy straws
have been generated. The method has been extensively validated with
a detection limit of 100ng/ml for morphine. Quantitative scoring of
capillary
electrophoresis peak areas and retention times for the profiles may
be used to authenticate and assess sample quality.
Pharmacognosy: activity
Ali et al (King’s College London) investigate the potential anti-diabetic
properties of Malaysian local plants using in vitro models, and isolate
the compounds responsible for the activity using bioassay-guided fractionation
techniques. The most active extract is the hexane extract of Phyllanthus
amarus, which has a significant inhibitory effect. The hexane extract
is fractionated by preparative thin layer chromatography. Five fractions
are collected and tested in the bioassay to obtain the most active component.
Fang and Houghton (King’s College London) select five traditional
Chinese medicines, four plants and one animal, for research into their
reputed anti-cancer effects. Chloroform extracts of Illicium verum fruits,
Lonicera japonica flowers and Aristolochia manshuriensis stem show considerable
cytotoxicity; the chloroform extract of I verum is selectively cytotoxic
for lung cancer.
McCurrie et al (University of Bradford) note that populations consuming
diets rich in phytoestrogens appear to have reduced cardiovascular disease
risks, and they investigate the possible mechanism by which phytoestrogens
relax blood vessels. A comparison is made of relaxant actions of genistein,
a tyrosine kinase inhibitor and its analogue daidzein with those of the
endogenous oestradiol. The authors conclude that relaxation elicited
by phytoestrogens does not depend on the presence of endothelium in all
types of blood vessel.
Cheung et al (King’s College London and Institute of Soil Science
and Plant Cultivation, Pulawy, Poland) report for the first time on the
activity of saponins from Medicago species against dermatophytes. Total
saponins were separately obtained from roots and aerial parts of M
sativa,
M murex, M arabica and M hybrida. Four isolated glycosides of medicagenic
acid, one of hederagenin and one of soyasapogenol were also available
and all eight extracts and six compounds were tested against three species
of dermatophytic fungi. Trichophyton tonsurans appears to be the most
sensitive of the dematophytes to the active compounds. Glycosides of
medicagenic acid are the most active compounds, especially the 3-O-glucoside.
TLC analysis of the extracts shows no clear correlation between content
of identifiable compounds and activity although many compounds present
are unidentified.
Simulation and computing
Naylor et al (GlaxoSmithKline and TNO Pharma, The Netherlands) describe
and evaluate the TNO Intestinal Model (TIM), an in vitro model that
can mimic the dynamic conditions found within the stomach and small
intestine. The model can simulate fed conditions by introducing the
meal into the system itself and setting enzymic secretion conditions.
A dosage form is introduced into the model and samples are taken throughout
the run. Development work is carried out utilising the TIM and an immediate-release
paroxetine formulation. A prediction of the plasma profile is carried
out using the commercially available program GastroPLUS with TIM data
as input, providing an excellent tool to aid the selection of a formulation
in pharmaceutical development.
Burke et al (University of Sunderland and Robert Gordon University,
Aberdeen) are designing more efficient chiral stationary phases by
modelling the
interaction of hexahelicenes with chiral analytes. The energies obtained
from the modelling show good agreement with the experimentally derived
data and the most favourable energy corresponded to compounds with the
longest retention times. The promise of delivery of drugs by the transdermal
route remains largely unrealised because for many drug molecules the
skin constitutes a significant barrier. A greater understanding of the
mechanism of action of penetration enhancers could assist in their rational
design.
Notman et al (King’s College London and Unilever Research & Development)
investigate the possible mechanisms of action of oleic acid in a lipid
system using molecular simulation and confirm that the oleic acid molecules
do indeed interact with the hydrocarbon chains of the lipid bilayer.
Oleic acid disperses throughout the bilayer without forming a separate
lipid phase. Although a range of solubility-enhancing formulation types
exists, there is little published information about how to choose the
most suitable formulation types for a given drug.
Branchu et al (AstraZeneca R&D) build a data set from AstraZeneca
proprietary drugs as well as substances and suitable formulations taken
from the literature. The properties included pKa, molecular weight, melting
point, octanol/water distribution coefficient, number of hydrogen-bond
donor and acceptor groups, dose and dose-to-solubility ratio. The data
set was then examined using principal component analysis resulting in
the identification of latent variables highlighting the presence of structure
in the data. Certain compounds, such as nifedipine, played little part
in influencing the principal components. Other compounds, such as chlorzoxazone,
made a greater contribution. The study suggests that empirical approaches
combining multivariate projection and case-based reasoning may be applicable
in dosage form development. Interest in the use of artificial neural
networks for the modelling of pharmaceutical formulations has increased
during the past decade, and numerous commercial programs are available.
Plumb et al (University of Bradford and UMIST) study the effect of varying
the training algorithm on the predictive ability of three programs: InForm
(Intelligensys), CAD/Chem (AI Ware) and the Neural Network Toolbox (The
MathWorks). An immediate release tablet formulation data set comprising
205 records is used. Choice of training algorithm and hidden layer architecture
is shown to exert a significant effect on predictive ability. Nevertheless
different packages are capable of generating equivalent models provided
that both training algorithm and hidden layer architecture are optimised.
Buggins and Taylor (Welsh School of Pharmacy) make an ambitious attempt
to correlate calculated solubility and molecular connectivity indices
of some phenothiazines and angiotensin converting enzyme inhibitors with
their absorption, distribution and elimination. Both solubility and connectivity
indices appear to have potential, as several correlations are found with
the pharmacokinetic parameters. However, the same correlations are not
seen for both groups of drugs, suggesting that consideration of several
physicochemical and molecular parameters is the best strategy for determining
quantitative structure-pharmacokinetic relationships.
Spectroscopy: near-infrared
Near-infrared spectroscopy provides a quick and accurate alternative
to a reference analytical method such as HPLC, which allows for increased
testing frequency and greater process knowledge and understanding,
and facilitates the move of quality systems towards continuous verification.
Smith et al (School of Pharmacy, University of London, and Pfizer
Ltd) demonstrate the feasibility of a single-tablet near-infrared assay
for atorvastatin in Lipitor tablets, a significant challenge due
to
the low concentration of atorvastatin present.
Morton et al (Abbott Laboratories and School of Pharmacy, University
of London) report the use of near-infrared spectroscopy to measure
the limit of detection of caffeine in sucrose powders. The limit
of detection
is dependent on the variability of particle size fractions of the substrate
and strategies to improve this can enable lower values to be obtained.
Spectroscopy: Raman spectroscopy
Owen et al (Imperial College London) developed a novel biophotonics
technique using Raman spectroscopy to monitor the interaction of chemicals
with
cells non-invasively and in situ over a period of days. The technique
is demonstrated using etoposide. No changes were observed in the concentrations
of the components except for a decrease in DNA. Raman spectroscopy
was capable of modelling cellular changes in real-time and the potential
to analyse any cellular component makes the technique a powerful drug-screening
technology. The biophotonics cell monitoring system can speed up pharmaceutical
R&D by rapidly eliminating drug candidates that are deleterious
to human cells. It may eventually offer an alternative to some forms
of animal testing.
The simplest form of univariate imaging is not an option for unknown
mixtures so Sasic et al (Pfizer Global Research
and Development, Sandwich and University of Greenwich) analyse Raman
images of pharmaceutical products by sample-sample 2D correlation spectroscopy.
Comparison of this method with principal component analysis was found
satisfactory, encouraging the use of the technique as an initial approach
for producing chemical images of pharmaceutical samples.
Spectroscopy: ultrasonic spectroscopy
High-resolution ultrasonic spectroscopy is a new technique for material
analysis based on the measurement of high-frequency sound waves propagating
through samples, allowing direct probing of micro-structural organisation
and intermolecular forces. Dwyer et al (Ultrasonic Scientific, Dublin,
and University College Dublin) describe the application for direct
real-time monitoring of crystallisation of lysozyme, formation of
micro-emulsions, and the hydrolysis of maltodextrin by alpha-amylase.
The technology
is extremely sensitive, non-destructive, requires no markers and
can be used in non-transparent samples. |
The
Pharmaceutical Journal