Deep learning for in vitro prediction of pharmaceutical formulations

Current pharmaceutical formulation development still strongly relies on the traditional trial-and-error approach by individual experiences of pharmaceutical scientists, which is laborious, time-consuming and costly. Recently, deep learning has been widely applied in many challenging domains because of its important capability of automatic feature extraction. The aim of this research is to use deep learning to predict pharmaceutical formulations. In this paper, two different types of dosage forms were chosen as model systems. Evaluation criteria suitable for pharmaceutics were applied to assessing the performance of the models. Moreover, an automatic dataset selection algorithm was developed for selecting the representative data as validation and test datasets. Six machine learning methods were compared with deep learning. The result shows the accuracies of both two deep neural networks were above 80% and higher than other machine learning models, which showed good prediction in pharmaceutical formulations. In summary, deep learning with the automatic data splitting algorithm and the evaluation criteria suitable for pharmaceutical formulation data was firstly developed for the prediction of pharmaceutical formulations. The cross-disciplinary integration of pharmaceutics and artificial intelligence may shift the paradigm of pharmaceutical researches from experience-dependent studies to data-driven methodologies

Machine learning for the prediction of phenols cytotoxicity

Quantitative structure-activity relationships (QSAR) are relevant techniques that assist biologists and chemists in accelerating the drug design process and help understanding many biological and chemical mechanisms. Using classical statistical methods may affect the accuracy and the reliability of the developed QSAR models. This work aims to use a machine learning approach to establish a QSAR model for phenols cytotoxicity prediction. This issue concern many chemists and biologists. In this investigation, the dataset is diverse, and the cytotoxicity data are sparse. Multi-component description of the compounds has then been considered. A set of molecular descriptors fed the deep neural network (DNN) and served to train the DNN. The established DNN model was able to predict the cytotoxicity of the phenols at high precision. The correlation coefficient at the fitting stage was higher than other statistical methods reported in the literature or developed in the present work, specifically multiple linear regression (MLR) and shallow artificial neural networks (ANN), and was equal to 0.943. The predictive capability of the model, as estimated by the coefficient of determination on an external predictive dataset, was significantly high and was about 0.739. This finding could help implement many molecular descriptors relevant to describing the compounds, representing the effects governing the phenols' cytotoxicity toward Tetrahymena pyriformis, avoiding overfitting and outlier exclusion

Android skin cancer detection and classification based on MobileNet v2 model

The latest developments in the smartphone-based skin cancer diagnosis application allow simple ways for portable melanoma risk assessment and diagnosis for early skin cancer detection. Due to the trade-off problem (time complexity and error rate) on using a smartphone to run a machine learning algorithm for image analysis, most of the skin cancer diagnosis apps execute the image analysis on the server. In this study, we investigate the performance of skin cancer images detection and classification on android devices using the MobileNet v2 deep learning model. We compare the performance of several aspects; object detection and classification method, computer and android based image analysis, image acquisition method, and setting parameter. Skin cancer actinic Keratosis and Melanoma are used to test the performance of the proposed method. Accuracy, sensitivity, specificity, and running time of the testing methods are used for the measurement. Based on the experiment results, the best parameter for the MobileNet v2 model on android using images from the smartphone camera produces 95% accuracy for object detection and 70% accuracy for classification. The performance of the android app for object detection and classification model was feasible for the skin cancer analysis. Android-based image analysis remains within the threshold of computing time that denotes convenience for the user and has the same performance accuracy with the computer for the high-quality images. These findings motivated the development of disease detection processing on android using a smartphone camera, which aims to achieve real-time detection and classification with high accuracy

Accelerating 3D printing of pharmaceutical products using machine learning

[Abstract] Three-dimensional printing (3DP) has seen growing interest within the healthcare industry for its ability to fabricate personalized medicines and medical devices. However, it may be burdened by the lengthy empirical process of formulation development. Active research in pharmaceutical 3DP has led to a wealth of data that machine learning could utilize to provide predictions of formulation outcomes. A balanced dataset is critical for optimal predictive performance of machine learning (ML) models, but data available from published literature often only include positive results. In this study, in-house and literature-mined data on hot melt extrusion (HME) and fused deposition modeling (FDM) 3DP formulations were combined to give a more balanced dataset of 1594 formulations. The optimized ML models predicted the printability and filament mechanical characteristics with an accuracy of 84%, and predicted HME and FDM processing temperatures with a mean absolute error of 5.5 °C and 8.4 °C, respectively. The performance of these ML models was better than previous iterations with a smaller and a more imbalanced dataset, highlighting the importance of providing a structured and heterogeneous dataset for optimal ML performance. The optimized models were integrated in an updated web-application, M3DISEEN, that provides predictions on filament characteristics, printability, HME and FDM processing temperatures, and drug release profiles (https://m3diseen.com/predictionsFDM/). By simulating the workflow of preparing FDM-printed pharmaceutical products, the web-application expedites the otherwise empirical process of formulation development, facilitating higher pharmaceutical 3DP research throughput

Pregled primene algoritama mašinskog učenja u farmaceutskoj tehnologiji

Machine learning algorithms, and artificial intelligence in general, have a wide range of applications in the field of pharmaceutical technology. Starting from the formulation development, through a great potential for integration within the Quality by design framework, these data science tools provide a better understanding of the pharmaceutical formulations and respective processing. Machine learning algorithms can be especially helpful with the analysis of the large volume of data generated by the Process analytical technologies. This paper provides a brief explanation of the artificial neural networks, as one of the most frequently used machine learning algorithms. The process of the network training and testing is described and accompanied with illustrative examples of machine learning tools applied in the context of pharmaceutical formulation development and related technologies, as well as an overview of the future trends. Recently published studies on more sophisticated methods, such as deep neural networks and light gradient boosting machine algorithm, have been described. The interested reader is also referred to several official documents (guidelines) that pave the way for a more structured representation of the machine learning models in their prospective submissions to the regulatory bodies.Algoritmi mašinskog učenja, kao i veštačka inteligencija u širem smislu, su veoma značajni i primenjuju se u razne svrhe u okviru farmaceutske tehnologije. Počevši od razvoja formulacija, preko izuzetnog potencijala za integraciju u koncept dizajna kvaliteta (engl. Quality by design), algoritmi mašinskog učenja omogućavaju bolje razumevanje uticaja kako formulacionih faktora tako i odgovarajućih procesnih parametara. Algoritmi mašinskog učenja mogu biti od naročitog značaja i za analizu velikog obima podataka koji se generišu korišćenjem procesnih analitičkih tehnologija. U ovom radu su ukratko predstavljene veštačke neuronske mreže, kao jedan od najčešće korišćenih algoritama mašinskog učenja. Prikazani su procesi treninga i testiranja mreža, kao i ilustrativni primeri algoritama primenjenih za različite potrebe razvoja i/ili optimizacije farmaceutskih formulacija i postupaka njihove izrade. Takođe, dat je i pregled budućih trendova u ovoj oblasti, kao i novijih studija o sofisticiranim metodama, poput dubokih neuronskih mreža, i light gradient boosting algoritma. Zainteresovani čitaoci se takođe upućuju na nekoliko zvaničnih dokumenata (vodiča), po uzoru na koje mogu da se očekuju i preporuke za strukturiranu prezentaciju modela mašinskog učenja koji će se podnositi regulatornim telima u okviru dokumentacije koja se priprema za potrebe registracije novih lekova

Harnessing machine learning for development of microbiome therapeutics

The last twenty years of seminal microbiome research has uncovered microbiota's intrinsic relationship with human health. Studies elucidating the relationship between an unbalanced microbiome and disease are currently published daily. As such, microbiome big data have become a reality that provide a mine of information for the development of new therapeutics. Machine learning (ML), a branch of artificial intelligence, offers powerful techniques for big data analysis and prediction-making, that are out of reach of human intellect alone. This review will explore how ML can be applied for the development of microbiome-targeted therapeutics. A background on ML will be given, followed by a guide on where to find reliable microbiome big data. Existing applications and opportunities will be discussed, including the use of ML to discover, design, and characterize microbiome therapeutics. The use of ML to optimize advanced processes, such as 3D printing and in silico prediction of drug-microbiome interactions, will also be highlighted. Finally, barriers to adoption of ML in academic and industrial settings will be examined, concluded by a future outlook for the field

Machine learning models for the prediction of pharmaceutical powder properties

Error on title page – year of award is 2023.Understanding how particle attributes affect the pharmaceutical manufacturing process performance remains a significant challenge for the industry, adding cost and time to the development of robust products and production routes. Tablet formation can be achieved by several techniques however, direct compression (DC) and granulation are the most widely used in industrial operations. DC is of particular interest as it offers lower-cost manufacturing and a streamlined process with fewer steps compared with other unit operations. However, to achieve the full potential benefits of DC for tablet manufacture, this places strict demands on material flow properties, blend uniformity, compactability, and lubrication, which need to be satisfied. DC is increasingly the preferred technique for pharmaceutical companies for oral solid dose manufacture, consequently making the flow prediction of pharmaceutical materials of increasing importance. Bulk properties are influenced by particle attributes, such as particle size and shape, which are defined during crystallization and/or milling processes. Currently, the suitability of raw materials and/or formulated blends for DC requires detailed characterization of the bulk properties. A key goal of digital design and Industry 4.0 concepts is through digital transformation of existing development steps be able to better predict properties whilst minimizing the amount of material and resources required to inform process selection during early- stage development. The work presented in Chapter 4 focuses on developing machine learning (ML) models to predict powder flow behaviour of routine, widely available pharmaceutical materials. Several datasets comprising powder attributes (particle size, shape, surface area, surface energy, and bulk density) and flow properties (flow function coefficient) have been built, for pure compounds, binary mixtures, and multicomponent formulations. Using these datasets, different ML models, including traditional ML (random forest, support vector machines, k nearest neighbour, gradient boosting, AdaBoost, Naïve Bayes, and logistic regression) classification and regression approaches, have been explored for the prediction of flow properties, via flow function coefficient. The models have been evaluated using multiple sampling methods and validated using external datasets, showing a performance over 80%, which is sufficiently high for their implementation to improve manufacturing efficiency. Finally, interpretability methods, namely SHAP (SHapley Additive exPlanaitions), have been used to understand the predictions of the machine learning models by determining how much each variable included in the training dataset has contributed to each final prediction. Chapter 5 expanded on the work presented in Chapter 4 by demonstrating the applicability of ML models for the classification of the viability of pharmaceutical formulations for continuous DC via flow function coefficient on their powder flow. More than 100 formulations were included in this model and the particle size and particle shape of the active pharmaceutical ingredients (APIs), the flow function coefficient of the APIs, and the concentration of the components of the formulations were used to build the training dataset. The ML models were evaluated using different sampling techniques, such as bootstrap sampling and 10-fold cross-validation, achieving a precision of 90%. Furthermore, Chapter 6 presents the comparison of two data-driven model approaches to predict powder flow: a Random Forest (RF) model and a Convolutional Neural Network (CNN) model. A total of 98 powders covering a wide range of particle sizes and shapes were assessed using static image analysis. The RF model was trained on the tabular data (particle size, aspect ratio, and circularity descriptors), and the CNN model was trained on the composite images. Both datasets were extracted from the same characterisation instrument. The data were split into training, testing, and validation sets. The results of the validation were used to compare the performance of the two approaches. The results revealed that both algorithms achieved a similar performance since the RF model and the CNN model achieved the same accuracy of 55%. Finally, other particle and bulk properties, i.e., bulk density, surface area, and surface energy, and their impact on the manufacturability and bioavailability of the drug product are explored in Chapter 7. The bulk density models achieved a high performance of 82%, the surface area models achieved a performance of 80%, and finally, the surface-energy models achieved a performance of 60%. The results of the models presented in this chapter pave the way to unified guidelines moving towards end-to-end continuous manufacturing by linking the manufacturability requirements and the bioavailability requirements.Understanding how particle attributes affect the pharmaceutical manufacturing process performance remains a significant challenge for the industry, adding cost and time to the development of robust products and production routes. Tablet formation can be achieved by several techniques however, direct compression (DC) and granulation are the most widely used in industrial operations. DC is of particular interest as it offers lower-cost manufacturing and a streamlined process with fewer steps compared with other unit operations. However, to achieve the full potential benefits of DC for tablet manufacture, this places strict demands on material flow properties, blend uniformity, compactability, and lubrication, which need to be satisfied. DC is increasingly the preferred technique for pharmaceutical companies for oral solid dose manufacture, consequently making the flow prediction of pharmaceutical materials of increasing importance. Bulk properties are influenced by particle attributes, such as particle size and shape, which are defined during crystallization and/or milling processes. Currently, the suitability of raw materials and/or formulated blends for DC requires detailed characterization of the bulk properties. A key goal of digital design and Industry 4.0 concepts is through digital transformation of existing development steps be able to better predict properties whilst minimizing the amount of material and resources required to inform process selection during early- stage development. The work presented in Chapter 4 focuses on developing machine learning (ML) models to predict powder flow behaviour of routine, widely available pharmaceutical materials. Several datasets comprising powder attributes (particle size, shape, surface area, surface energy, and bulk density) and flow properties (flow function coefficient) have been built, for pure compounds, binary mixtures, and multicomponent formulations. Using these datasets, different ML models, including traditional ML (random forest, support vector machines, k nearest neighbour, gradient boosting, AdaBoost, Naïve Bayes, and logistic regression) classification and regression approaches, have been explored for the prediction of flow properties, via flow function coefficient. The models have been evaluated using multiple sampling methods and validated using external datasets, showing a performance over 80%, which is sufficiently high for their implementation to improve manufacturing efficiency. Finally, interpretability methods, namely SHAP (SHapley Additive exPlanaitions), have been used to understand the predictions of the machine learning models by determining how much each variable included in the training dataset has contributed to each final prediction. Chapter 5 expanded on the work presented in Chapter 4 by demonstrating the applicability of ML models for the classification of the viability of pharmaceutical formulations for continuous DC via flow function coefficient on their powder flow. More than 100 formulations were included in this model and the particle size and particle shape of the active pharmaceutical ingredients (APIs), the flow function coefficient of the APIs, and the concentration of the components of the formulations were used to build the training dataset. The ML models were evaluated using different sampling techniques, such as bootstrap sampling and 10-fold cross-validation, achieving a precision of 90%. Furthermore, Chapter 6 presents the comparison of two data-driven model approaches to predict powder flow: a Random Forest (RF) model and a Convolutional Neural Network (CNN) model. A total of 98 powders covering a wide range of particle sizes and shapes were assessed using static image analysis. The RF model was trained on the tabular data (particle size, aspect ratio, and circularity descriptors), and the CNN model was trained on the composite images. Both datasets were extracted from the same characterisation instrument. The data were split into training, testing, and validation sets. The results of the validation were used to compare the performance of the two approaches. The results revealed that both algorithms achieved a similar performance since the RF model and the CNN model achieved the same accuracy of 55%. Finally, other particle and bulk properties, i.e., bulk density, surface area, and surface energy, and their impact on the manufacturability and bioavailability of the drug product are explored in Chapter 7. The bulk density models achieved a high performance of 82%, the surface area models achieved a performance of 80%, and finally, the surface-energy models achieved a performance of 60%. The results of the models presented in this chapter pave the way to unified guidelines moving towards end-to-end continuous manufacturing by linking the manufacturability requirements and the bioavailability requirements