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Nanocraft AI

Advanced AI-powered nanoformulation design platform for pharmaceutical development. Design, optimize, and validate nanocarrier systems with cutting-edge computational tools for drug delivery research and development.

AI-Powered

Advanced machine learning algorithms for optimization

DoE Integration

Statistical design of experiments for robust formulations

Real-time Modeling

Predictive models for formulation optimization

Protocol Generation

Automated pharmaceutical-grade protocol creation

Getting Started

Step-by-Step Workflow
1
Define Compound

Input your active pharmaceutical ingredient (API) using chemical name, SMILES, or InChI. AI resolves molecular properties automatically.

2
Select Technique

Choose optimal nanoformulation technique based on AI scoring and molecular properties analysis.

3
Design Experiments

Generate statistically robust experimental designs using advanced DoE methodologies.

4
Optimize & Scale

Use Bayesian optimization to find optimal conditions and generate manufacturing protocols.

Key Features
  • PubChem integration for automatic molecular property retrieval
  • AI-powered technique scoring and selection
  • Advanced statistical design of experiments (DoE)
  • Dual modeling approach (Elastic Net + Gaussian Process)
  • Bayesian optimization for multi-objective formulation
  • Pharmaceutical-grade protocol generation
  • Real-time correlation analysis and model validation
  • Interactive chat interface for protocol refinement
Terms and Conditions - Important Disclaimer
Research Use Only
  • This platform is intended for research and development purposes only
  • Not intended for direct clinical use or patient treatment
  • Results require validation through appropriate experimental methods
  • Compliance with institutional safety guidelines is required
Data & Safety
  • Users are responsible for data accuracy and interpretation
  • Follow all applicable regulatory guidelines (FDA, EMA, ICH)
  • Ensure proper laboratory safety protocols are followed
  • Validate all computational predictions experimentally

Terms of Use

Academic & Commercial Use: This platform incorporates advanced AI and computational methods. Users should cite appropriate sources and respect intellectual property rights. For commercial applications, ensure compliance with relevant licensing requirements.

By using this platform, you acknowledge and agree to these terms and understand the research-only nature of this tool.

Compound Resolution
Technique Scoring
Design Space Generation

Generate experimental design space for your selected technique.

Experiments Management

DoE Parameters
Bayesian Optimization

Optimize your formulation using advanced Bayesian methods.

Protocol Generation

NanoCraft AI - Scientific Documentation

Overview

NanoCraft AI is a comprehensive, open-source platform designed to accelerate nanocarrier development through AI-driven computational techniques. The platform integrates physicochemical analysis, formulation technique scoring, design of experiments (DoE), machine learning modeling, and Bayesian optimization to guide pharmaceutical scientists from compound characterization to optimized nanoformulation protocols.

Core Capabilities
  • Intelligent Compound Analysis: Automated physicochemical property extraction and enhancement
  • Multi-Criteria Technique Scoring: Evidence-based ranking of 15+ formulation approaches
  • Adaptive Design Spaces: Context-aware parameter range generation
  • Statistical DoE Generation: Classical and optimal experimental designs
  • Predictive Modeling: Multi-response regression with model comparison
  • Bayesian Optimization: Iterative parameter refinement
  • Protocol Generation: Detailed, equipment-specific manufacturing procedures

1. Nanoprecipitation (Polymer-Based)

Principle: Controlled precipitation of polymer-drug conjugates through solvent displacement in a non-solvent environment.

Mechanism: Drug and polymer dissolved in water-miscible organic solvent → Rapid injection into aqueous antisolvent → Instantaneous nucleation via Marangoni effect → Particle growth controlled by Ostwald ripening inhibition.

Optimal Applications: Hydrophobic drugs (log P > 2), BCS Class II/IV compounds, Polymer MW: 5,000-50,000 Da, Drug loading: 5-40% w/w, Particle size: 50-300 nm

Critical Parameters: Organic:aqueous ratio (1:2 to 1:10), Injection rate (0.5-10 mL/min), Stirring speed (200-1500 rpm), Temperature (15-40°C)

2. Liposome Formation via Ethanol Injection

Principle: Spontaneous lipid self-assembly through rapid ethanol dilution below critical aggregation concentration.

Mechanism: Phospholipids dissolved in ethanol → Rapid injection creates local supersaturation → Lipid monomers aggregate into bilayer sheets → Vesicle closure forms unilamellar liposomes.

Optimal Applications: Both hydrophilic (core) and hydrophobic (bilayer) drugs, pH-sensitive formulations, Drug loading: 5-30% for hydrophilic, up to 50% for hydrophobic

Critical Parameters: Ethanol:water ratio (1:3 to 1:20), Lipid concentration (1-50 mg/mL), Temperature (25-65°C, above Tm), Cholesterol content (0-50 mol%)

3. Lipid Nanoparticles (LNPs)

Principle: Ionizable lipid-based nanostructures for nucleic acid delivery with pH-responsive endosomal escape.

Mechanism: Microfluidic mixing induces lipid self-assembly → Ionizable lipids complex with nucleic acids at acidic pH → pH-triggered membrane fusion enables cytoplasmic delivery.

Optimal Applications: mRNA vaccines and therapeutics, siRNA/miRNA delivery, Gene editing cargo (CRISPR), Particle size: 60-120 nm, Encapsulation efficiency: 80-95%

Critical Parameters: Ionizable lipid pKa (6.0-6.8), N/P ratio (3-6), Flow rate ratio (3:1 to 12:1), Mixing pH (3.5-4.5)

4. Microfluidic Mixing

Principle: Controlled nanoprecipitation through precise fluid manipulation in microchannels with predictable mixing dynamics.

Mechanism: Chaotic advection in herringbone mixers → Diffusion-dominated mixing at low Reynolds numbers → Rapid solvent exchange (milliseconds) → Uniform supersaturation prevents polydispersity.

Optimal Applications: LNPs and liposomes, Polymeric nanoparticles, Scalable GMP manufacturing, Size control: 20-500 nm

Critical Parameters: Flow rate ratio (1:1 to 20:1), Total flow rate (0.5-20 mL/min), Residence time (10-1000 ms), Temperature control (±0.5°C)

5. Solid Lipid Nanoparticles (SLNs)

Principle: Drug incorporation in solid lipid matrix providing controlled release and improved stability.

Mechanism: Hot homogenization disperses molten lipid phase → High-pressure creates nanoemulsion → Controlled cooling crystallizes lipid core → Drug trapped in lipid crystal lattice.

Optimal Applications: Lipophilic drugs (log P 2-7), Oral bioavailability enhancement, Sustained/controlled release, Brain targeting, Particle size: 50-1000 nm

Critical Parameters: Homogenization pressure (100-2000 bar), Temperature (5-10°C above lipid Tm), Surfactant concentration (0.5-5%), Number of cycles (3-10)

6. Nanoemulsions (Low Energy Methods)

Principle: Spontaneous emulsification through phase transitions without external energy input.

Mechanism: Phase inversion temperature (PIT) method → Ultralow interfacial tension (<10⁻³ mN/m) → Thermodynamically driven droplet formation.

Optimal Applications: Lipophilic drugs (log P > 3), Oral bioavailability enhancement, Topical/transdermal delivery, Droplet size: 20-200 nm

Critical Parameters: HLB value optimization (8-18), PIT determination (40-90°C), Oil:surfactant:water ratio, Cooling/dilution rate

7. Spray Drying

Principle: Rapid solvent evaporation from atomized droplets producing solid particles with controlled morphology.

Mechanism: Two-fluid or rotary atomization → Droplet drying in hot gas stream → Surface enrichment and crust formation → Cyclone separation and collection.

Optimal Applications: Inhalation formulations (1-5 μm), Solid dispersions for oral delivery, Protein/peptide stabilization, Particle size: 0.1-100 μm

Critical Parameters: Inlet temperature (100-220°C), Outlet temperature (40-100°C), Feed rate (2-50 mL/min), Atomization pressure/speed

8. Polymeric Micelles

Principle: Amphiphilic block copolymer self-assembly above critical micelle concentration forming core-shell nanostructures.

Mechanism: Entropy-driven hydrophobic aggregation → Core-shell architecture formation → Drug solubilization in hydrophobic core → Steric stabilization by hydrophilic corona.

Optimal Applications: Poorly soluble drugs (log P > 2), Tumor targeting via EPR effect, Stimuli-responsive drug release, Size range: 10-100 nm

Critical Parameters: CMC (10⁻⁷ to 10⁻⁴ M), Drug:polymer ratio (0.05-0.5 w/w), Temperature (20-60°C), Ionic strength effects

9. Dendrimers

Principle: Monodisperse, hyperbranched macromolecules with defined architecture for precise drug conjugation/encapsulation.

Mechanism: Generation-dependent size growth → Interior cavities for drug encapsulation → Surface groups for conjugation → pH-responsive protonation behavior.

Optimal Applications: Small molecule drugs (<1000 Da), Gene delivery (polycationic dendrimers), Targeted therapy, Imaging agents, Size range: 2-15 nm

Critical Parameters: Generation number (G0-G10), Core type and functionality, Surface group modification, Drug:dendrimer ratio, pH optimization (6.5-7.8)

10. Nanosuspension Wet Milling

Principle: Top-down particle size reduction through mechanical attrition in liquid medium with stabilizers.

Mechanism: Impact and shear forces fracture crystals → Stabilizer adsorption prevents aggregation → Ostwald ripening inhibition → Size reduction follows first-order kinetics.

Optimal Applications: BCS Class II/IV drugs, Immediate release formulations, Injectable nanosuspensions, Ophthalmic delivery, Size range: 100-2000 nm

Critical Parameters: Milling media size (0.1-2 mm), Drug concentration (5-40% w/w), Milling speed (200-1500 rpm), Milling time (0.5-72 hours)

11. Supercritical Fluid Processing

Principle: Exploiting unique properties of supercritical CO₂ for particle formation and drug encapsulation.

Mechanism: Rapid expansion (RESS) induces nucleation → Anti-solvent precipitation (SAS/GAS) → Tunable solvent properties → Solvent-free processing.

Optimal Applications: Thermolabile compounds, Inhalation particles, Controlled morphology, Organic solvent-free processing, Size range: 50-5000 nm

Critical Parameters: Pressure (75-400 bar), Temperature (31-80°C), CO₂ flow rate, Nozzle geometry, Co-solvent addition (0-20%)

12. Electrospray Encapsulation

Principle: Electrostatic atomization of polymer solutions forming mono-disperse particles through coulombic fission.

Mechanism: Taylor cone formation at needle tip → Jet breakup via varicose instability → Coulombic fission creates droplets → Solvent evaporation during flight.

Optimal Applications: Protein/peptide encapsulation, Core-shell particles, Living cell encapsulation, Controlled release matrices, Size range: 100 nm - 100 μm

Critical Parameters: Applied voltage (5-30 kV), Flow rate (0.01-10 mL/h), Needle-collector distance (5-30 cm), Solution conductivity, Polymer concentration (1-30% w/v)

13. Layer-by-Layer Assembly

Principle: Sequential adsorption of oppositely charged polyelectrolytes building multilayer films on template particles.

Mechanism: Electrostatic attraction drives adsorption → Charge overcompensation enables alternation → Interpenetration creates stable layers → Template dissolution yields hollow capsules.

Optimal Applications: Multi-drug delivery systems, Stimuli-responsive release, Surface functionalization, Enzyme immobilization, Size range: 50 nm - 10 μm

Critical Parameters: Polyelectrolyte MW and charge density, pH (affects ionization), Ionic strength (0.01-1 M), Deposition time (1-30 min), Number of layers (2-50)

14. Self-Emulsifying Drug Delivery Systems (SEDDS)

Principle: Spontaneous emulsification of lipid formulations upon aqueous dilution forming drug-loaded nanoemulsions.

Mechanism: Surfactant migration to oil-water interface → Rapid dispersion without external energy → Fine emulsion formation (SMEDDS <100 nm) → Enhanced drug solubilization.

Optimal Applications: BCS Class II drugs (optimal), BCS Class IV drugs (good), Oral bioavailability enhancement, Reduced food effect, First-pass metabolism bypass

Critical Parameters: Oil selection (log P 2-7), Surfactant HLB (12-18), Co-surfactant ratio, Drug loading (5-30% w/w), Dilution ratio (1:50 to 1:1000)

15. Micellization via Solvent Displacement

Principle: Rapid solvent exchange triggers amphiphile aggregation into thermodynamically stable micelles.

Mechanism: Solvent miscibility creates supersaturation → Nucleation above CMC → Growth via monomer addition → Equilibration to optimal aggregation number.

Optimal Applications: Hydrophobic drug solubilization, Injectable formulations, Ophthalmic delivery, Small molecule encapsulation, Size range: 5-100 nm

Critical Parameters: CMC determination, Solvent selection (DMSO, DMF, ethanol), Mixing rate and method, Final solvent content (<5%), Temperature effects on CMC

NanoCraft AI employs a sophisticated scoring algorithm evaluating techniques across multiple weighted criteria:

1. Physicochemical Compatibility (Weight: 30%)

Log P Matching:

Score = exp(-0.5 × ((log P - optimal_log P) / σ)²)

Optimal log P values by technique:

  • Nanoprecipitation: 3.5 (σ = 1.2)
  • Liposomes: 1.0 (σ = 2.0)
  • LNPs: 4.0 (σ = 1.5) for small molecules, any for nucleic acids
  • SLNs: 4.5 (σ = 1.5)
  • Nanoemulsions: 4.5 (σ = 1.0)
  • Micelles: 3.5 (σ = 1.5)
  • SEDDS: 4.0 (σ = 1.5)
  • Dendrimers: 2.0 (σ = 2.0)
  • Spray drying: 2.5 (σ = 2.5)
  • Wet milling: 4.0 (σ = 2.0)
BCS Classification Integration:
  • Class I: Focus on controlled release techniques
  • Class II: Prioritize solubilization (SEDDS, micelles, nanoemulsions)
  • Class III: Emphasize permeation enhancement
  • Class IV: Combine solubilization and permeation strategies
2. Manufacturing Complexity (Weight: 25%)

Process Scalability Scores:

  • Nanoprecipitation: 0.9 (simple mixing)
  • Microfluidic mixing: 0.8 (continuous process)
  • Nanoemulsions: 0.7 (low energy favorable)
  • Spray drying: 0.7 (established scale-up)
  • SEDDS: 0.9 (simple mixing)
  • Wet milling: 0.6 (time-intensive)
  • Liposomes: 0.5 (multi-step)
  • LNPs: 0.6 (specialized equipment)
  • SLNs: 0.4 (high-pressure homogenization)
  • Supercritical: 0.3 (specialized equipment)
3. Target Delivery Route (Weight: 20%)

Route-Specific Multipliers:

  • Oral: SEDDS (1.5×), SLNs (1.3×), nanoemulsions (1.2×), spray drying (1.1×)
  • Intravenous: Liposomes (1.4×), LNPs (1.3×), micelles (1.2×), dendrimers (1.1×)
  • Pulmonary: Spray drying (1.5×), liposomes (1.3×), SLNs (1.1×)
  • Topical: Nanoemulsions (1.5×), SLNs (1.3×), liposomes (1.1×)
  • Ocular: Nanoemulsions (1.3×), micelles (1.2×), dendrimers (1.1×)
4. Stability Profile (Weight: 15%)

Stability Ranking (1.0 = most stable):

  • Spray dried particles: 0.95
  • SEDDS (anhydrous): 0.90
  • SLNs: 0.85
  • Dendrimers: 0.85
  • Nanosuspensions: 0.75
  • Polymeric nanoparticles: 0.75
  • LNPs: 0.70 (frozen storage)
  • Nanoemulsions: 0.65
  • Liposomes: 0.60
  • Micelles: 0.55
5. Development Timeline (Weight: 10%)

Time-to-Clinic Estimates:

  • Fast track (6-12 months): Nanoprecipitation, SEDDS, micelles
  • Standard (12-18 months): Liposomes, LNPs, nanoemulsions
  • Extended (18-24 months): Dendrimers, layer-by-layer, electrospray
Dynamic Scoring Adjustments
final_score = base_score × (1 + Σ(objective_weight_i × compatibility_i))

Objective modifiers:

  • Nucleic acid delivery: LNPs +0.5, liposomes +0.3
  • Sustained release: SLNs +0.4, spray drying +0.3, layer-by-layer +0.3
  • Rapid onset: Nanoemulsions +0.3, micelles +0.3, nanosuspensions +0.3
  • Bioavailability enhancement: SEDDS +0.5, SLNs +0.3, nanoemulsions +0.3
  • Targeted delivery: Liposomes +0.4, micelles +0.3, dendrimers +0.3

Experimental Design Selection
1. Full Factorial Designs

Application: Complete exploration with ≤4 factors

Structure:

Runs = 2^k × replicates + center_points
Power analysis: α = 0.05, β = 0.20, effect size = 2σ

Example for LNP optimization (2³ design):

  • Factor A: Ionizable lipid % (35-50 mol%)
  • Factor B: Flow rate ratio (3:1 to 12:1)
  • Factor C: N/P ratio (3-6)
  • Responses: Size, PDI, encapsulation efficiency, transfection
2. Fractional Factorial Designs

Resolution Selection:

  • Resolution III: Screening (main effects clear)
  • Resolution IV: Main effects + key interactions
  • Resolution V: Full interaction assessment

Generator Selection:

2^(7-2) Resolution IV: I = ABCEF = BCDEG
Alias structure prevents main-interaction confounding
3. Central Composite Designs (CCD)

Rotatability and Orthogonality:

α = (2^k)^(1/4) for rotatability
α = √k for orthogonal blocking

Face-Centered CCD for constrained spaces:

  • α = 1 keeps points within factor ranges
  • Suitable for formulation with strict bounds
4. Box-Behnken Designs

Advantages:

  • No corner points (avoids extreme combinations)
  • Fewer runs than CCD for 3-4 factors
  • Rotatable or nearly rotatable

Application Example - Liposome Optimization:

  • 3 factors, 15 runs (including 3 center points)
  • Efficient for quadratic model fitting
  • Excellent for sequential optimization
5. Optimal Designs

D-Optimal Criterion:

Maximize |X'X| → Minimize average prediction variance
G-efficiency = (p/n) × 100 / max(leverage)

I-Optimal for Prediction:

Minimize ∫(variance of ŷ)dχ over design space
Better for response surface prediction
Statistical Analysis Framework
Response Surface Methodology (RSM)

Hierarchical Model Building:

1. Linear model: Y = β₀ + Σβᵢxᵢ
2. Add interactions: + ΣΣβᵢⱼxᵢxⱼ
3. Add quadratic: + Σβᵢᵢxᵢ²

Model Diagnostics:

  • Lack of fit test: F = MS_lof / MS_pe
  • Adjusted R²: Penalizes overfitting
  • Predicted R²: Cross-validation metric
  • Cook's distance: Influential observations
Multi-Response Optimization

Desirability Function:

Individual: dᵢ = [(yᵢ - Lᵢ)/(Tᵢ - Lᵢ)]^r
Overall: D = (∏dᵢ^wᵢ)^(1/Σwᵢ)

Pareto Optimization:

  • Non-dominated solutions
  • Trade-off visualization
  • Decision maker preferences

Model Architecture Selection
1. Elastic Net Regression

Regularization Balance:

Loss = MSE + α[ρ||β||₁ + (1-ρ)||β||₂²/2]
α: regularization strength
ρ: L1/L2 ratio (typically 0.5)

Advantages:

  • Handles multicollinearity
  • Feature selection via L1
  • Grouped variable selection
  • Interpretable coefficients
2. Gaussian Process Regression

Kernel Selection for Formulation:

Matérn 5/2: k(x,x') = σ²(1 + √5r + 5r²/3)exp(-√5r)
r = ||x - x'||/ℓ

Hyperparameter Optimization:

  • Length scales indicate factor importance
  • Noise parameter estimates experimental error
  • Automatic relevance determination (ARD)
3. Random Forest

Formulation-Specific Tuning:

  • Trees: 500-1000 for stable importance
  • Max depth: √(n_features) to 2×√(n_features)
  • Min samples split: 5-10% of data
  • Bootstrap with OOB error estimation
4. Gradient Boosting

XGBoost Parameters:

Learning rate: 0.01-0.1
Max depth: 3-6
Subsample: 0.7-0.9
Colsample: 0.7-0.9
Early stopping patience: 50 rounds
Feature Engineering

Physicochemical Descriptors:

  • Molecular: MW, logP, logD, pKa, PSA, HBD/HBA
  • Structural: Aromatic rings, rotatable bonds, stereocenter
  • Electronic: HOMO/LUMO, dipole moment, polarizability

Process Parameters:

  • Dimensionless groups (Reynolds, Weber, Peclet numbers)
  • Interaction terms (concentration × temperature)
  • Polynomial features for curvature
  • Time-based features for kinetics
Model Validation

Cross-Validation Strategies:

  • Time series split for stability data
  • Group k-fold for batch effects
  • Nested CV for hyperparameter selection
  • Monte Carlo CV for small datasets
Performance Metrics
RMSE: √(Σ(yᵢ - ŷᵢ)²/n)
MAE: Σ|yᵢ - ŷᵢ|/n
MAPE: 100 × Σ|yᵢ - ŷᵢ|/yᵢ/n
R²: 1 - SS_res/SS_tot
Q²: Cross-validated R²

Acquisition Functions
1. Expected Improvement (EI)
EI(x) = (μ(x) - f⁺ - ξ)Φ(Z) + σ(x)φ(Z)
Z = (μ(x) - f⁺ - ξ)/σ(x)
ξ: exploration parameter (0.01 typical)
2. Knowledge Gradient
KG(x) = E[max_x' μⁿ⁺¹(x') | xⁿ⁺¹ = x] - max_x' μⁿ(x')
  • Accounts for future decisions
  • Better for expensive experiments
3. Entropy Search
  • Maximizes information gain about optimum location
  • Robust to GP hyperparameter uncertainty
Constraint Handling

Probabilistic Constraints:

P(g(x) ≤ 0) = Φ(-μ_g(x)/σ_g(x))
EIC(x) = EI(x) × ∏P(gᵢ(x) ≤ 0)

Examples:

  • Particle size: 50 ≤ size ≤ 200 nm
  • PDI: PDI < 0.3
  • Yield: yield > 70%
  • Stability: degradation < 5% at 30 days
Multi-Objective Optimization

Hypervolume Improvement:

HVI = ∫_S I(y)p(y|x)dy
S: dominated space

Scalarization Methods:

  • Weighted sum: Simple but misses non-convex regions
  • Tchebycheff: f = max(wᵢ|fᵢ - zᵢ*|)
  • Boundary intersection: Systematic Pareto exploration

Quality by Design (QbD) Framework
Critical Quality Attributes (CQAs)

Nanoparticle Systems:

  • Particle size and distribution
  • Drug loading and encapsulation efficiency
  • Release kinetics
  • Physical/chemical stability
  • Biocompatibility markers
Critical Process Parameters (CPPs)

Risk Assessment Matrix:

RPN = Severity × Occurrence × Detection
High risk: RPN > 100, Medium: 50 < RPN ≤ 100, Low: RPN ≤ 50
Process Analytical Technology (PAT)

In-Line Measurements:

  • Particle Sizing: FBRM, Spatial filtering velocimetry
  • Chemical Composition: NIR spectroscopy, Raman spectroscopy
Process Control
u(t) = Kp×e(t) + Ki×∫e(t)dt + Kd×de/dt
PID tuning via Ziegler-Nichols or model-based
Regulatory Considerations
ICH Guidelines Compliance
  • Q8(R2) Pharmaceutical Development: Enhanced approach documentation, Design space justification
  • Q9 Quality Risk Management: FMEA for process risks, Fault tree analysis
  • Q10 Pharmaceutical Quality System: Knowledge management, Change management
  • Q11 Development and Manufacture: Starting material selection, Process validation approach
Regulatory Submission Components
  • Design space definition and justification
  • Control strategy documentation
  • Risk assessment matrices
  • Process validation protocols
  • Analytical method validation
  • Stability study protocols
Platform Navigation

Use the main navigation tabs to access specific workflow sections. Each section contains detailed tools and explanations for compound analysis, technique scoring, experimental design, and protocol generation. The platform guides you through the complete nanoformulation development process from initial compound characterization to optimized manufacturing protocols.

Design of Experiments (DoE)
Experimental Design Selection
1. Full Factorial Designs

Application: Complete exploration with ≤4 factors

Structure:

Runs = 2^k × replicates + center_points
Power analysis: α = 0.05, β = 0.20, effect size = 2σ
2. Fractional Factorial Designs

Resolution Selection:

  • Resolution III: Screening (main effects clear)
  • Resolution IV: Main effects + key interactions
  • Resolution V: Full interaction assessment
3. Central Composite Designs (CCD)

Rotatability and Orthogonality:

α = (2^k)^(1/4) for rotatability
α = √k for orthogonal blocking
4. Box-Behnken Designs

Advantages:

  • No corner points (avoids extreme combinations)
  • Fewer runs than CCD for 3-4 factors
  • Rotatable or nearly rotatable
5. Optimal Designs

D-Optimal Criterion:

Maximize |X'X| → Minimize average prediction variance
G-efficiency = (p/n) × 100 / max(leverage)

I-Optimal for Prediction:

Minimize ∫(variance of ŷ)dχ over design space
Response Surface Methodology (RSM)

Hierarchical Model Building:

Linear model: Y = β₀ + Σβᵢxᵢ
Add interactions: + ΣΣβᵢⱼxᵢxⱼ
Add quadratic: + Σβᵢᵢxᵢ²
Multi-Response Optimization

Desirability Function:

Individual: dᵢ = [(yᵢ - Lᵢ)/(Tᵢ - Lᵢ)]^r
Overall: D = (∏dᵢ^wᵢ)^(1/Σwᵢ)
Machine Learning & Predictive Modeling
Model Architecture Selection
1. Elastic Net Regression

Regularization Balance:

Loss = MSE + α[ρ||β||₁ + (1-ρ)||β||₂²/2]
α: regularization strength, ρ: L1/L2 ratio (typically 0.5)
2. Gaussian Process Regression

Kernel Selection for Formulation:

Matérn 5/2: k(x,x') = σ²(1 + √5r + 5r²/3)exp(-√5r)
r = ||x - x'||/ℓ
3. Random Forest

Formulation-Specific Tuning:

  • Trees: 500-1000 for stable importance
  • Max depth: √(n_features) to 2×√(n_features)
  • Min samples split: 5-10% of data
  • Bootstrap with OOB error estimation
Feature Engineering

Physicochemical Descriptors:

  • Molecular: MW, logP, logD, pKa, PSA, HBD/HBA
  • Structural: Aromatic rings, rotatable bonds, stereocenter
  • Electronic: HOMO/LUMO, dipole moment, polarizability

Process Parameters:

  • Dimensionless groups (Reynolds, Weber, Peclet numbers)
  • Interaction terms (concentration × temperature)
  • Polynomial features for curvature
  • Time-based features for kinetics
Performance Metrics
RMSE: √(Σ(yᵢ - ŷᵢ)²/n)
MAE: Σ|yᵢ - ŷᵢ|/n
R²: 1 - SS_res/SS_tot
Q²: Cross-validated R²
Bayesian Optimization
Acquisition Functions
1. Expected Improvement (EI)
EI(x) = (μ(x) - f⁺ - ξ)Φ(Z) + σ(x)φ(Z)
Z = (μ(x) - f⁺ - ξ)/σ(x)
ξ: exploration parameter (0.01 typical)
2. Knowledge Gradient
KG(x) = E[max_x' μⁿ⁺¹(x') | xⁿ⁺¹ = x] - max_x' μⁿ(x')
  • Accounts for future decisions
  • Better for expensive experiments
Constraint Handling

Probabilistic Constraints:

P(g(x) ≤ 0) = Φ(-μ_g(x)/σ_g(x))
EIC(x) = EI(x) × ∏P(gᵢ(x) ≤ 0)

Examples:

  • Particle size: 50 ≤ size ≤ 200 nm
  • PDI: PDI < 0.3
  • Yield: yield > 70%
  • Stability: degradation < 5% at 30 days
Multi-Objective Optimization
HVI = ∫_S I(y)p(y|x)dy
S: dominated space
Quality by Design (QbD) Framework
Critical Quality Attributes (CQAs)

Nanoparticle Systems:

  • Particle size and distribution
  • Drug loading and encapsulation efficiency
  • Release kinetics
  • Physical/chemical stability
  • Biocompatibility markers
Critical Process Parameters (CPPs)

Risk Assessment Matrix:

RPN = Severity × Occurrence × Detection
High risk: RPN > 100, Medium: 50 < RPN ≤ 100, Low: RPN ≤ 50
Process Analytical Technology (PAT)

In-Line Measurements:

  • Particle Sizing: FBRM, Spatial filtering velocimetry
  • Chemical Composition: NIR spectroscopy, Raman spectroscopy
Process Control
u(t) = Kp×e(t) + Ki×∫e(t)dt + Kd×de/dt
PID tuning via Ziegler-Nichols or model-based
Regulatory Considerations
ICH Guidelines Compliance
  • Q8(R2) Pharmaceutical Development: Enhanced approach documentation, Design space justification
  • Q9 Quality Risk Management: FMEA for process risks, Fault tree analysis
  • Q10 Pharmaceutical Quality System: Knowledge management, Change management
  • Q11 Development and Manufacture: Starting material selection, Process validation approach
Regulatory Submission Components
  • Design space definition and justification
  • Control strategy documentation
  • Risk assessment matrices
  • Process validation protocols
  • Analytical method validation
  • Stability study protocols
Platform Navigation

Use the main navigation tabs to access specific workflow sections. Each section contains detailed tools and explanations for compound analysis, technique scoring, experimental design, and protocol generation. The platform guides you through the complete nanoformulation development process from initial compound characterization to optimized manufacturing protocols.