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Whole-exome and targeted sequencing of 13 individuals from 10 unrelated families with overlapping clinical manifestations identified loss-of-function and missense variants in KIAA1109 allowing delineation of an autosomal-recessive multi-system syndrome, which we suggest to name Alkuraya-Kučinskas syndrome (MIM 617822). Shared phenotypic features representing the cardinal characteristics of this syndrome combine brain atrophy with clubfoot and arthrogryposis. Affected individuals present with cerebral parenchymal underdevelopment, ranging from major cerebral parenchymal thinning with lissencephalic aspect to moderate parenchymal rarefaction, severe to mild ventriculomegaly, cerebellar hypoplasia with brainstem dysgenesis, and cardiac and ophthalmologic anomalies, such as microphthalmia and cataract. Severe loss-of-function cases were incompatible with life, whereas those individuals with milder missense variants presented with severe global developmental delay, syndactyly of 2 nd and 3 rd toes, and severe muscle hypotonia resulting in incapacity to stand without support. Consistent with a causative role for KIAA1109 loss-of-function/hypomorphic variants in this syndrome, knockdowns of the zebrafish orthologous gene resulted in embryos with hydrocephaly and abnormally curved notochords and overall body shape, whereas published knockouts of the fruit fly and mouse orthologous genes resulted in lethality or severe neurological defects reminiscent of the probands' features.

Histone lysine methyltransferases (KMTs) and demethylases (KDMs) underpin gene regulation. Here we demonstrate that variants causing haploinsufficiency of KMTs and KDMs are frequently encountered in individuals with developmental disorders. Using a combination of human variation databases and existing animal models, we determine 22 KMTs and KDMs as additional candidates for dominantly inherited developmental disorders. We show that KMTs and KDMs that are associated with, or are candidates for, dominant developmental disorders tend to have a higher level of transcription, longer canonical transcripts, more interactors, and a higher number and more types of post-translational modifications than other KMT and KDMs. We provide evidence to firmly associate KMT2C, ASH1L, and KMT5B haploinsufficiency with dominant developmental disorders. Whereas KMT2C or ASH1L haploinsufficiency results in a predominantly neurodevelopmental phenotype with occasional physical anomalies, KMT5B mutations cause an overgrowth syndrome with intellectual disability. We further expand the phenotypic spectrum of KMT2B-related disorders and show that some individuals can have severe developmental delay without dystonia at least until mid-childhood. Additionally, we describe a recessive histone lysine-methylation defect caused by homozygous or compound heterozygous KDM5B variants and resulting in a recognizable syndrome with developmental delay, facial dysmorphism, and camptodactyly. Collectively, these results emphasize the significance of histone lysine methylation in normal human development and the importance of this process in human developmental disorders. Our results demonstrate that systematic clinically oriented pathway-based analysis of genomic data can accelerate the discovery of rare genetic disorders.

Rheology is the study of how materials deform and flow as a result of an external force, and is one tool that is used by formulators to help characterize semisolid dosage forms. The two extremes of rheological behavior are elastic and viscous (or plastic) behavior. Between elastic and viscous behavior lies the real world of most substances, which are viscoelastic materials. In the case of viscoelastic materials, timescales are important to rheological behavior—when deformation is fast, materials exhibit solid-like behavior; when deformation is slow, materials exhibit fluid-like behavior. The rheology of semisolid formulations provides critical information for product and process performance, including product stability. Rheology-based measurements can help predict which formulations might exhibit flocculation, coagulation, or coalescence, resulting in undesired effects such as settling, creaming, or separation. Viscosity is a measure of the resistance of a material to flow, and is just one aspect of the rheological profile of a formulation.

Different semisolid dosage forms and various excipients used in pharmaceutical formulations are discussed. The current approach of the US Food Drug Administration for the classification of semisolid dosages is presented. The formation and formulation of emulsions are discussed in detail. The formulation of liposomes, one of the major drug-delivery systems used in pharmaceutical dosages, is also discussed.

Current trends are to use newer, targeted drug-delivery approaches to effectively deliver smaller dosages to target sites—thereby reducing toxicity and possible unwanted side effects. Different drug-delivery systems including emulsions, liposomes, and nanodrug delivery systems are reviewed and discussed. Methods of producing liposomes, and some existing drug products based on liposomes, are presented.

Both optical and electron microscopy techniques are discussed in relation to pharmaceutical formulation development. Microscopy is a very useful tool in pharmaceutical research, formulation development, process development, and quality control of manufactured products. Microscopy is routinely used for the examination of the drug material (the API—Active Pharmaceutical Ingredient), excipients (inactive ingredients present in the finished dosages), or the drug product. Both particle size and morphology are key characteristics for product performance; morphology is particularly important for aerosol dosage forms, in which particle flow is critical. Microscopes that use illumination sources in the ultraviolet the infrared regions are also available, and their application in pharmaceutical product development is gaining popularity. The importance of electron microscopes (both scanning and transmission) is discussed and the application of atomic force microscopy in pharmaceutical research has been pointed out.

Many types of aerosol products exist—such as deodorants, antiperspirants, hair sprays, insecticides, oils, polishes, and paints. The pressurized metered-dose inhaler is one type of aerosol product that is used to deliver drugs as a mist or spray via the pulmonary system. The common formulation types used for aerosol and nasal spray products are solutions, suspensions, and emulsions. This chapter looks at the manufacturing processes for aerosol and nasal spray products, the types of excipients that are used in aerosol and nasal spray formulations, and the effect that the excipients can have on the physical characteristics of the expelled product.

Polymers are extremely versatile ingredients in semisolid formulations, being used to create a range of different effects, from thickening to preservation and conditioning. Polymers are macromolecules consisting of a long-chain backbone of smaller repeating units (monomers) and side groups. Polymers that contain only a single type of repeat unit are known as homopolymers, whereas polymers containing a mixture of repeat units are known as copolymers. Depending on the type of polymer, the backbone can be either linear or branched. The side groups influence the functional properties of the polymer, such as how well it thickens, conditions, and forms films.

This chapter covers test methods typically used to evaluate and characterize semisolid formulations. The methods have been subdivided into physical, chemical, and microbiological, as well as separating them into tests that might typically be performed on all semisolid formulations, and those that are specific to a type of product. When they are performed during the product lifetime, and what information they can provide, is also described.

This chapter provides an overview of surfactants and surface properties that play important roles in pharmaceutical formulations. Examples of ionic, nonionic, and zwitterionic surfactants are provided. Structures of different lipids and their applications as excipients or actives are discussed. A brief introduction to the HLB system is provided. Examples of drug products in the marketplace that use various surfactants and lipids are listed indicating the importance of surfactants and lipids in pharmaceutical formulations. Surface and interfacial tension measurement, and the significance of the role of surface tension and contact angle in designing the pharmaceutical formulations has been discussed.

Although the regulatory landscape for pharmaceutical semisolid products is well established, the regulations are under constant review to improve the quality, safety, and efficacy of products both under development and in the marketplace. This chapter highlights some of the development/quality guidance in place at the time of writing and, more importantly, provides references to where the most up-to-date compliance information can be obtained.

Liquid and semisolid formulations contain many different functional ingredients depending on their physical form and intended use—for example, pH buffers, antioxidants, microbial preservatives, chelators, osmolality agents, penetration enhancers, thickeners, emulsifiers, solvent systems, humectants, pharmaceutically active ingredients, moisturizers, fragrances, flavorings, and colorants. When and how these ingredients are added to the formulation will determine whether the finished formulation is successful—aesthetically, functionally, and stable. This chapter looks at how formulations are typically put together, gives examples of different mixing systems, shows how Quality by Design can be applied to formulation development, and how to evaluate the stability of a formulation.

A generic modelling framework for phase transition catalyst based reacting systems has been developed and converted into a software tool. The modelling framework accommodates models of different types representing different sub-systems of the PTC-based reactive system; databases of model parameters and carefully collected and checked (for thermodynamic consistency) experimentally measured data. The models, data and software have been tested on various PTC-based reactive systems. Illustrative examples are provided.