ABSTRACT
In many manufacturing and research areas, the ability to accurately monitor and characterize nanoparticles is becoming increasingly important. Nanoparticle tracking analysis is rapidly becoming a standard method for this characterization, yet several key factors in data acquisition and analysis may affect results. Nanoparticle tracking analysis is prone to user input and bias on account of a high number of parameters available, contains a limited analysis volume, and individual sample characteristics such as polydispersity or complex protein solutions may affect analysis results. This study systematically addressed these key issues. The integrated syringe pump was used to increase the sample volume analyzed. It was observed that measurements recorded under flow caused a reduction in total particle counts for both polystyrene and protein particles compared to those collected under static conditions. In addition, data for polydisperse samples tended to lose peak resolution at higher flow rates, masking distinct particle populations. Furthermore, in a bimodal particle population, a bias was seen toward the larger species within the sample. The impacts of filtration on an agitated intravenous immunoglobulin sample and operating parameters including "MINexps" and "blur" were investigated to optimize the method. Taken together, this study provides recommendations on instrument settings and sample preparations to properly characterize complex samples.
Subject(s)
Immunoglobulins/analysis , Nanoparticles/analysis , Dynamic Light Scattering/methods , Particle Size , Polystyrenes/analysis , Protein AggregatesABSTRACT
Progress made through technological advances in drug discovery can be undermined by problems with measurement equipment, but it is often difficult to detect the issues without a specific investigation. This article describes the fundamentals of measurement systems analysis and focuses on the issue of precision. Three case studies are given where measurement systems were found to be flawed when subjected to a systematic analysis, and examples of the approaches needed for correction are described.
Subject(s)
Drug Discovery , Quality Control , ResearchABSTRACT
A range of 3,4-alkylated five-membered ring derivatives of gabapentin were synthesised. One compound (21) had an excellent level of potency against alpha(2)delta and was profiled in in vivo models of pain and anxiety.
Subject(s)
Amines/chemistry , Amino Acids/chemical synthesis , Anti-Anxiety Agents/chemical synthesis , Cyclohexanecarboxylic Acids/chemistry , Cyclopentanes/chemical synthesis , gamma-Aminobutyric Acid/chemistry , Amines/chemical synthesis , Amines/pharmacokinetics , Amino Acids/chemistry , Amino Acids/pharmacology , Animals , Anti-Anxiety Agents/chemistry , Anti-Anxiety Agents/pharmacokinetics , Cyclohexanecarboxylic Acids/chemical synthesis , Cyclohexanecarboxylic Acids/pharmacokinetics , Cyclopentanes/chemistry , Cyclopentanes/pharmacology , Disease Models, Animal , Gabapentin , Hyperalgesia/chemically induced , Hyperalgesia/drug therapy , Rats , gamma-Aminobutyric Acid/chemical synthesis , gamma-Aminobutyric Acid/pharmacokineticsABSTRACT
A range of 3-alkylated five-membered ring derivatives of Gabapentin were synthesized and several were found to have good levels of potency against the alpha2delta calcium subunit of a voltage-gated calcium channel. Two compounds were profiled in in vivo models of pain and anxiety.
Subject(s)
Amines/chemical synthesis , Amino Acids/chemical synthesis , Anti-Anxiety Agents/chemical synthesis , Cyclohexanecarboxylic Acids/chemical synthesis , Cyclopentanes/chemical synthesis , gamma-Aminobutyric Acid/chemical synthesis , Amines/chemistry , Amines/pharmacology , Amino Acids/chemistry , Amino Acids/pharmacology , Animals , Anti-Anxiety Agents/chemistry , Anti-Anxiety Agents/pharmacology , Calcium Channels/metabolism , Carrageenan/pharmacology , Cyclohexanecarboxylic Acids/chemistry , Cyclohexanecarboxylic Acids/pharmacology , Cyclopentanes/chemistry , Cyclopentanes/pharmacology , Gabapentin , Hyperalgesia/chemically induced , Hyperalgesia/drug therapy , Rats , Stereoisomerism , gamma-Aminobutyric Acid/chemistry , gamma-Aminobutyric Acid/pharmacologyABSTRACT
Synthesis of a number of bicyclic five-membered ring derivatives of gabapentin led to the identification of two compounds, (-)-(11A) and (20A) which both had an excellent level of potency against alpha(2)delta and were profiled in an in vivo model of neuropathic pain.
Subject(s)
Amines/chemical synthesis , Amino Acids/chemical synthesis , Bridged Bicyclo Compounds/chemical synthesis , Cyclohexanecarboxylic Acids/chemical synthesis , gamma-Aminobutyric Acid/chemical synthesis , Amines/chemistry , Amines/pharmacokinetics , Amino Acids/chemistry , Amino Acids/pharmacokinetics , Animals , Blood-Brain Barrier/metabolism , Bridged Bicyclo Compounds/chemistry , Bridged Bicyclo Compounds/pharmacokinetics , CHO Cells , Cricetinae , Cricetulus , Cyclohexanecarboxylic Acids/chemistry , Cyclohexanecarboxylic Acids/pharmacokinetics , Gabapentin , Neuralgia/drug therapy , Pain Measurement , Rats , Stereoisomerism , Structure-Activity Relationship , gamma-Aminobutyric Acid/chemistry , gamma-Aminobutyric Acid/pharmacokineticsABSTRACT
The SAR of a series of novel pyrido[3,4-d]pyramid-4-ylamine mGluR1 antagonists is described. The multiple of the unbound K(i) in cerebrospinal fluid necessary to give morphine like analgesic effects in an electromyograph pinch model in rodents is determined and the effect of structure on CNS penetration examined.
Subject(s)
Excitatory Amino Acid Antagonists/chemical synthesis , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Animals , Electromyography/methods , Excitatory Amino Acid Antagonists/chemistry , Excitatory Amino Acid Antagonists/pharmacology , Pain Measurement/drug effects , Pain Measurement/methods , Rats , Receptors, Metabotropic Glutamate/physiology , Structure-Activity RelationshipABSTRACT
Bringing drugs to the market remains a costly and, until now, often unpredictable challenge. Although understanding the underlying science is key to further progress, our imperfect knowledge of disease and complex biological systems leaves excellence in execution as the most tangible lever to sustain our serendipitous approach to drug discovery. The problems encountered in pharmaceutical R&D are not unique, but to learn from other industries it is important to recognise similarity, rather than differences, and to advance industrialisation of R&D beyond technology and automation. Tools like Lean and Six Sigma, already applied to increase business excellence across diverse organisations, can equally be introduced to pharmaceutical R&D and offer the potential to transform operations without large-scale investment.
