Mapping inequalities in exclusive breastfeeding in low- and middle-income countries, 2000–2018

Exclusive breastfeeding (EBF)—giving infants only breast-milk for the first 6 months of life—is a component of optimal breastfeeding practices effective in preventing child morbidity and mortality. EBF practices are known to vary by population and comparable subnational estimates of prevalence and progress across low- and middle-income countries (LMICs) are required for planning policy and interventions. Here we present a geospatial analysis of EBF prevalence estimates from 2000 to 2018 across 94 LMICs mapped to policy-relevant administrative units (for example, districts), quantify subnational inequalities and their changes over time, and estimate probabilities of meeting the World Health Organization’s Global Nutrition Target (WHO GNT) of ≥70% EBF prevalence by 2030. While six LMICs are projected to meet the WHO GNT of ≥70% EBF prevalence at a national scale, only three are predicted to meet the target in all their district-level units by 2030

EFFECT OF COMPRESSION FORCES ON THE STRUCTURAL STABILITY OF AMORPHOUS SYSTEMS

The failure of most new chemical entities to reach the market is mainly due to their drugability problems. The main causes of their drugability problem is poor bioavailability as the result of poor solubility or/and poor permeability through the GI wall. Various formulation strategies showed their capability to improve the kinetic solubility and dissolution rate of poorly water soluble drugs. The general introduction section merely focused on solid form modifications as a formulation strategy for poorly water soluble drugs. Solid dispersions are comparably discussed in detail including their preparation methods, stabilization mechanisms and the hurdles for the success of ASD in commercialized drug products with elaborate literature examples. Alternate solid forms, polymorphic forms and amorphous forms can also lead to differences in molecular, particulate and bulk level properties of the drug which can affect the bioavailability and processability of the drug. Therefore the relation of solid forms on physicochemical properties is also discussed briefly with practical examples. In addition, the solid form of drugs may also change during manufacturing which is briefly covered in the introduction section. An overview of pharmaceutical tableting, popular models to study the volume-pressure relation during compression and the mechanism and the consequences of plastic deformation of glassy polymers are also discussed.The general and specific objectives are further pointed out in chapter 2. The main objective of the project was to understand the role of compression on the structural and physical stability of amorphous solid dispersions and amorphous forms of pure drug. The glass forming properties and the glass stability of the amorphous form of pure drugs may play a role on the physical stability of amorphous solid dispersions. Indomethacin is a good glass former with relatively good physical stability. Amorphous indomethacin was prepared by cooling the molten sample rapidly (25°C/min) or slowly (0.2°C/min) to room temperature. The experimental protocols were devoid of stresses applied during sample transfer and preparation for analysis since compression and further analysis by thermal, vibrational spectroscopy and PXRD techniques were performed in the primary containers (DSC standard aluminum pan). Amorphous indomethacin generated from the gamma polymorphic form showed aging time dependent non-isothermal crystallization first predominantly to the stable gamma form and then to the metastable alfa-form of crystalline indomethacin. However, it crystallized to the stable gamma-form after a long period of storage. Compression enhanced and also increased the overall crystallization of amorphous indomethacin as evidently shown with high heat of crystallisation and lower crystallisation temperature. The tendency of crystallisation to the metastable alfa-form was higher for amorphous indomethacin prepared by fast cooling than by slow cooling from the melt. However, enthalpy recovery with physical aging was not consistently correlated with the crystallization tendency of the compressed and the uncompressed amorphous indomethacin. The origin of the selective crystallization with physical aging was not clearly understood.Unfavorable storage conditions such as elevated temperature and humidity may lead to phase transformation of solid dispersions from amorphous to crystalline or/and separation to multiple amorphous domains. Amorphous solid dispersions' success in improving bioavailability has not been reflected in the number of marketed products due to physical stability problems. Tablets are the most popular dosage forms hence most of marketed drug products of solid dispersions are tablets and capsules. Compression is an important stage of tablet manufacturing and understanding its consequences such as segmental dynamics, structural and thermodynamic changes in solid dispersions has a vital role on the quality of the final product. In chapter 4, we investigated the effect of compression on amorphous-amorphous phase separation in solid dispersions. The effect of compression was overt on the metastable amorphous solid dispersions with 30% and 40% (w/w) drug loadings in NAP ̶ PVP K 25 compositions where two distinct Tgs or a wider single Tg were observed for compressed NAP ̶ PVP ASD. These may be ascribed to the distortion of drug-polymer specific interaction as evidently shown on the IR profile. Solid dispersions with low drug loading (20% w/w) showed no difference in the glass transition and also IR profile among compressed and uncompressed samples. This indicates that the relatively stable ASD with high polymer composition can withstand the effect of compression on the drug-polymer demixing.In chapter 5 the drug-polymer mixing across different locations of laboratory spray dryers (ProCepT Micro-spray dryer and Buchi mini spray dryer B191) was investigated for various compositions of NAP ̶ PVP-VA 64 and miconazole ̶ PVP-VA 64 amorphous and partially crystalline solid dispersions. Surprisingly the drug-polymer mixing with solid dispersions varied across spray dryers. The solid dispersion with high NAP loading (50 % (w/w)) showed differences in percent crystallinity of the drug for samples collected from different locations which increased with physical aging below the Tg. Both the PXRD diffuse diffraction patterns and vibrational spectroscopic data showed differences which may arise from dissimilarities in drug-polymer mixing and level of interactions in NAP ̶ PVP-VA solid dispersions collected from different locations with spray dryers.The influence of compression was investigated for NAP/PVP-VA 64 solid dispersions collected from a single location which is covered in chapter 6. The glass transition width of the ASD was intact with compression without noticeable changes. However, a slight difference in PXRD diffuse halo diffraction pattern was observed among the compressed and uncompressed samples. The drug-polymer interaction was enhanced after compression for metastable NAP/PVP-VA amorphous solid dispersions (30% (w/w) drug loading) as revealed by FTIR which was manifested as lesser crystallinity compared to the uncompressed solid dispersions during storage. Compression led to amorphous-amorphous phase separation of NAP/PVP amorphous solid dispersion. On the contrary compression showed no clear change in drug-polymer mixing in NAP/PVP-VA ASD where the physical stability was improved for the compressed solid dispersion of NAP/PVP-VA. To understand further the role of deformation on drug-polymer interactions, we described in chapter 7 how DRS was used to probe molecular dynamics of pure PVP-VA before and after compression which will be a preliminary study to investigate the role of compression induced alterations in localised bond motions and segmental mobility with respect to drug-polymer interactions. PVP-VA showed predominant plastic deformation during tableting with low yield pressure, comparable to the most popular plastically deforming polymers used in pharmaceutical applications (e.g. MCC). Compression of PVP-VA appeared to lead to a shorter time scale for the secondary (ß) relaxation process and synchronous shift in relaxation peaks of both the localised bond motion and the segmental mobility. A similar secondary relaxation process was also observed for PVP which may indicate the source of the relaxation peak could be conformational transitions in the vinyl pyrrolidone moiety of PVP-VA. An additional wing was also identified for compressed PVP-VA with the primary relaxation peak with a mean relaxation time smaller than the powder and the slightly compressed PVP-VA. It likely suggests that compression induced heterogeneity in the segmental dynamics and also reduced the time scale of the relaxation process. The diffuse PXRD pattern of PVP-VA was markedly altered by compression as a result of a disparity in molecular packing. This study indicates that local bonds of PVP-VA involved in intermolecular interaction with NAP in the ASD can be significantly affected by compression. The general discussion with literature examples and the future perspective of the project are described in chapter 8.nrpages: 166status: publishe

Influence of Compression Forces on the Structural Stability of Naproxen/PVP-VA 64 Solid Dispersions

Solid dispersions are preferentially formulated as solid dosage forms such as tablets and capsules. The structural stability of the solid dispersions has not been adequately explored during post spray drying manufacturing processes. In this paper, we describe the influence of compression forces on solid dispersions made up of naproxen and PVP-VA 64 prepared by spray drying. Compression of the solid dispersion containing 30% (w/w) of naproxen led to low intensity of the powder X-ray diffraction (PXRD) halo pattern maxima at 2θ = 16.11°, and the uncompressed samples also exhibit higher glass transition broadening than the compressed samples after 21 days storage at 75% RH at ambient temperature which indicates structural changes in the solid dispersion. The intensity of the vibration band at 1654 cm^–1 originating from the interaction between the hydrogen of the carboxylic acid moiety of NAP and the amide carbonyl moiety of PVP-VA 64 was increased for the compressed samples. The consequence of compression was further amplified after a long-term stability study (5 months) where the compressed 40 and 50% (w/w) NAP/PVP-VA 64 solid dispersions showed less crystallinity than the uncompressed samples. This suggests that compression improved the physical stability of the solid dispersions as a result of enhanced drug–polymer interactions

Drug–Polymer Miscibility across a Spray Dryer: A Case Study of Naproxen and Miconazole Solid Dispersions

The structural and physical stability of solid dispersions have not been adequately explored during spray drying manufacturing processes. In this study a wide range of compositions of naproxen/PVP-VA 64 (poly­(1-vinylpyrrolidone-<i>co</i>-vinyl acetate)) and miconazole/PVP-VA 64 solid dispersions prepared by different laboratory spray dryers were collected from various selected locations and used to investigate the drug–polymer mixing across spray dryers. Spray-dried dispersions with 30% (w/w) naproxen collected from the transport tube of the Pro-C-epT Microspray dryer showed the narrowest glass transition width, which apparently indicates the highest degree of drug–polymer mixing compared to the other locations. The intensity of the naproxen–PVP-VA 64 interaction peak at 1654 cm^–1 of IR spectra differs for solid dispersions (SDs) from the collector and transport tube of Pro-C-epT Microspray dryer with a higher intensity for the latter. Samples with 50% (w/w) naproxen loading collected from the cyclone and the cyclone steel part of the Buchi mini spray dryer showed a melting endotherm (<i>T</i>_m at 112.2 ± 0.8 °C and Δ<i>H</i>_f between 0.7 and 1.8 J/g), whereas samples from the cyclone tube to the drying chamber were devoid of crystalline material. The variations in drug–polymer mixing extend to miconazole/PVP-VA solid dispersions where 20% drug loading showed location-dependent drug–polymer mixing. This study clearly showed that the variation in drug–polymer miscibility and solid form of the drug in solid dispersions can occur across spray dryer in small-scale manufacturing processes. The optimization of formulation parameters and spray drying process parameters is imperative to diminish these variations to enhance homogeneity of solid dispersions in laboratory scale spray dryers. The same problem can occur in geometrically large spray drying manufacturing equipment, and the robustness of the processes should be carefully assessed

Modelling and understanding powder flow properties and compactability of selected active pharmaceutical ingredients, excipients and physical mixtures from critical material properties

The development of solid dosage forms and manufacturing processes are governed by complex physical properties of the powder and the type of pharmaceutical unit operation the manufacturing processes employs. Suitable powder flow properties and compactability are crucial bulk level properties for tablet manufacturing by direct compression. It is also generally agreed that small scale powder flow measurements can be useful to predict large scale production failure. In this study, predictive multilinear regression models were effectively developed from critical material properties to estimate static powder flow parameters from particle size distribution data for a single component and for binary systems. A multilinear regression model, which was successfully developed for ibuprofen, also efficiently predicted the powder flow properties for a range of batches of two other active pharmaceutical ingredients processed by the same manufacturing route. The particle size distribution also affected the compactability of ibuprofen, and the scope of this work will be extended to the development of predictive multivariate models for compactability, in a similar manner to the approach successfully applied to flow properties