Tonix Pharmaceuticals Holding Corp. · NASDAQ:TNXP

Tonix Pharmaceuticals — 11th Global Conference on Pharmaceutics and Novel Drug Delivery Systems (PDDS) 2024

46 slides from Tonix Pharmaceuticals's conference presentation, Sep 23, 2024

Slide 1: Mannitol as a eutectic forming agent for improved sublingual delivery of Cyclobenzaprine HCl
Redox ©2024 Mannitol as a eutectic forming agent for improved sublingual delivery of Cyclobenzapine HCl Prof. Marino Nebuloni 11 th Global Conference on Pharmaceutics and Novel Drug Delivery Systems (PDDS), Rome September 19, 2024. Oral Presentation.
Slide 2: Disclosures
Redox ©2024 Disclosures • Prof . Nebuloni is an employee of Redox Analytical Science Srl • Research funded by Tonix Pharmaceuticals, Inc . 2
Slide 3: Content
Redox ©2024 Content • Drug – excipient compatibility strategy • Eutectic solid state complex formation : benefit on dissolution profile and physical and chemical stability • Case study : Cyclobenzaprine HCl - excipient compatibility for sublingual drug product formulation • D - mannitol polymorphism
Slide 4: Compatibility strategy excipient impact
Redox ©2024 Compatibility strategy excipient impact 4 • Pharmaceutical excipients have important functions such as serving as carriers, improving drug stability, solubilization and increasing or slowing down the drug release . • The laws and regulatory agencies have made rigid regulations on the com
Slide 5: Thermodynamic parameters in API-Excipient interaction
Redox ©2024 Thermodynamic paramiters in API - Excipient interaction 5
Slide 6: Main Interaction and Physico-chemical Impact on API
Redox ©2024 Main Interaction and Physico - chemical Impact on API Solid state complex Dissolution Rate Stability or Degradation New Entity Interaction Excipient and API during the formulation 6
Slide 7: Drug Excipient Compatibility - Experimental Design
Redox ©2024 Drug Excipient Compatibility - Experimental Design - • Before initiating drug product development , the formulation scientist must fully consider the chemical structure of the API and the type of delivering system • Initial selection of excipients should be based on appropriate delivery
Slide 8: Analytical Methods for drug-excipient compatibility assessment
Redox ©2024 Analytical Methods for drug - excipient compatibility assessment • Thermal Methods (DSC, TGA, Hot Stage Micros .) • FT - IR Spectroscopy • X - Ray Powder Diffraction • Scanning Electron Microscopy (SEM) • Dissolution Rate profile & Intrinsic Dissolution Rate • NMR at the solid state 8
Slide 9: Drug-excipient compatibility screening: thermoanalytical and spectroscopic techniques
Redox ©2024 Drug – excipient compatibility screening — Role of thermoanalytical and spectroscopic techniques 9
Slide 11: Eutectic formation during interaction
Redox ©2024 Eutectic formation during interaction The eutectic formation in several cases can improve the cohesion between the particles and assure better physical bounding between the drug substance and the excipient . Nevertheless, the physical state prevents the erosion of the final dosage form .
Slide 12: Case Study: compatibility investigation in sublingual formulation TNX-102 SL
Redox ©2024 Case Study: compatibility investigation in sublingual formulation TNX - 102 SL ( Cyclobenzaprine HCl Sublingual Tablets ) 1 Tonix Pharmaceuticals Activity Fibromyalgia, Long COVID, Acute Stress Disorder…… 12 1 TNX - 102 SL is an experimental new drug and has not been approved for any ind
Slide 13: Formulation development of TNX-SL tablet - trial n°1
Redox ©2024 Formulation development of TNX - 102 SL tablet - trial n ° 1 - Component Studied Formulation (mg) Cyclobenzaprine HCl 2.8 D - mannitol 2.5 Perlitol Flash ( D - mannitol:corn starch ) 28.0 Crospovidone 2.0 Sodium Stearyl Fumarate 1.2 Colloidal silicon dioxide 1.0 Dibasic potassium phospha
Slide 14: Crystal Structure of Cyclobenzaprine.HCl
Redox ©2024 Crystal Structure of Cyclobenzaprine.HCl M.S. Siddegowda Acta Crystallogr Sect E Struct Rep Online. 2011 July 1; 67( Pt 7): 14 Cyclobenzaprine is a tricyclic approved in the U.S. for short - term use as a muscle relaxant. It works by blocking nerve impulses (or pain sensations) in the br
Slide 15: Physical Properties of Cyclobenzaprine HCl
Redox ©2024 Physical Properties of Cyclobenzaprine HCl Integral -213,07 mJ normalized -108,32 Jg^-1 Onset 215,31 °C Peak 218,60 °C Left Limit 210,63 °C Right Limit 223,74 °C 1,9670 mg CICLOBENZAPRINA STD Experiment Comments: 25.09.2017 15:59:56, Termo Analisi MARZIA PENDINO Method Name: 25..250 - 10
Slide 16: D-mannitol Polymorphic Forms
Redox ©2024 D - mannitol Poymorphic Forms Polymorphic Form Melting point ( ° C) Heat of melting (kJ/mole) Crystal system XRPD peak position (2 θ ) α alfa 166 52 orthorombic 13.6 ° - 17.2 ° β beta 166.4 53 orthorombic 10.4 ° - 14.6 ° - 23.4 ° δ delta 154 monoclinic 9.7 ° - 22.2 ° Thermal Stability 16
Slide 17: D-mannitol X ray comparison between the polymorphic forms
Redox ©2024 D - mannitol – X ray comparison between the polymorphic forms 17
Slide 18: D-mannitol crystallization and polymorphic transition
Redox ©2024 D - mannitol crystallization and polymorphic transition Optical microscopy polarized light Metastable phase nucleation Delta Form Delta to Beta Metastable + Delta + Beta Crystalline Beta Form 18
Slide 19: Compatibility procedure
Redox ©2024 Compatibility procedure CBP HCl + Excipients Mechanical mixture Wet granulation Spray Dry Mixture investigation 19
Slide 20: DSC Compatibility Results - mechanical mixtures
Redox ©2024 DSC Compatibility Results - mechanical mixtures - CBP HCl lubricant CBP HCl Crospov . CBP HCl K 2 HPO 4 CBP HCl Mannitol beta Eutectic 20
Slide 21: Results of Compatibility Screening Cyclobenzaprine HCl with each excipient by DSC
Redox ©2024 Results of Compatibility Screening Cyclobenzaprine HCl with each excipient by DSC Excipient Mixture with CBP HCl (1:1) Formulation ratio lubricant NO NO D mannitol (beta form ) Eutectic formation Eutectic formation Sicon Colloidal NO NO Crospovidone NO NO Potassium bibasic phosphate Acid
Slide 22: Eutectic formation between Cyclobenzaprine HCl and D-mannitol beta form
Redox ©2024 Eutectic formation between Cyclobenzaprine HCl and D - mannitol - beta form - DSC Eutectic ratio CBP HCl : D - mannitol (75:25) 22 eutectic
Slide 23: Phase Diagram Cyclobenzaprine HCl - D-mannitol (beta form)
Redox ©2024 Phase Diagram Cyclobenzaprine HCl – D - mannitol (beta form ) CBP HCl D mannitol (beta) Eutectic mp 143 ° C 23
Slide 24: Phase Diagram by Melting Enthalpy of the Eutectic
Redox ©2024 Phase Diagram by Melting Enthalpy of the Eutectic Eutectic ratio 75:25 24
Slide 26: XRPD of CBP HCl:D-mannitol mixtures
Redox ©2024 XRPD of CBP HCl:D - mannitol mixtures - no chemical interaction with new entity formation - 26
Slide 27: Compatibility by Wet Granulation
Redox ©2024 Compatibility by Wet Granulation CBP HCl – D - mannitol (beta) DSC mixtures Eutectic ratio CBP HCl : D - mannitol (75:25) 27
Slide 28: Eutectic Morphology by SEM
Redox ©2024 Eutectic Morphology by SEM of the mixtures mechanical wet granulation 28
Slide 29: C NMR on D-mannitol alone and in eutectic with Cyclobenzaprine HCl
Redox ©2024 C 13 NMR on D - mannitol alone and D - mannitol in eutectic with Cyclobenzaprine HCl Black: D - mannitol alone (beta form) Red: D - mannitol in eutectic: major component (shifted upfield ~ 1 ppm from D - mannitol alone) Blue: D - mannitol in eutectic: minor component (shifted upfield ~ 2
Slide 30: Screening by spray dry process to reduce eutectic particle size
Redox ©2024 Screening by spray dry process to reduce the eutectic particle size and improve the dissolution rate Water / ethanol solution CBP HCl + D mannitol Eutectic with D mannitol (beta Form) Eutectic with D mannitol (delta Form) 30
Slide 31: Cyclobenzaprine HCl : D mannitol delta form
Redox ©2024 Cyclobenzaprine HCl : D mannitol delta form ( eutectic - ratio 65:35) API:mannitol 75:25 SD (cicl), 3.5330 mg Integral -11.99 mJ normalized -3.40 Jg^-1 Onset 142.65 °C Peak 143.61 °C Left Limit 142.05 °C Right Limit 146.18 °C Integral -286.50 mJ normalized -81.09 Jg^-1 Onset 136.02 °C Pe
Slide 32: Phase Diagram Cyclobenzaprine HCl : D-mannitol (delta form)
Redox ©2024 Phase Diagram Cyclobenzaprine HCl : D - mannitol (delta form ) Eutectic mp 134 ° C 32
Slide 33: Comparison of Phase Diagrams (beta vs. delta)
Redox ©2024 Comparison of Phase Diagrams Cyclobenzaprine HCl – D mannitol ( beta vs. delta ) Red: beta mp.143 ° C Black: delta mp.134 ° C 33
Slide 34: Morphology of Eutectics by SEM (beta vs delta)
Redox ©2024 Morphology of Eutectics by SEM ( beta vs delta ) wet granulation D mannitol Beta form spray dry D mannitol delta form 34
Slide 36: Stability on the time of the two Eutectics
Redox ©2024 Stability on the time of the two Eutectics Eutectic CBP HCl : D - mannitol (75:25) beta Form To T 6 months T 12 months Eutectic CBP HCl : D - mannitol (65:35) delta Form time Stable Unstable 36
Slide 37: Eutectic stability in relation to the process
Redox ©2024 Eutectic stability in relation to the process Mechanical grinding Wet granulation spray dry D Mannitol polymorph • Stable • Less homogeneous • Large particles • Stable • Homogeneous • Small particles • Unstable • Small particles • Large porosity beta beta delta 37
Slide 38: Interaction of the eutectic with Dipotassium phosphate
Redox ©2024 Interaction of the eutectic with Dipotasium phosphate (K 2 HPO 4 ) The Screening Compatibility test shows degradation of the CBP HCl with possible free base formation ( CBP HCl+K 2 HPO 4  CBP + KCl + H2O+Phosphates) Cyclobenzaprine HCl K 2 HPO 4 Mix (1:1) CBP HCl + K 2 HPO 4 Chemical in
Slide 39: Proprietary Cyclobenzaprine HCl Eutectic stabilizes Transmucosal Sublingual Tablet Formulation
Redox ©2024 Proprietary Cyclobenzaprine HCl Eutectic stabilizes Transmucosal Sublingual Tablet Formulation 39
Slide 40: Influence of mouth pH on SL tablet dissolution
Redox ©2024 Influence of mouth pH on SL tablet dissolution and cyclobenzaprine free base formation No Compatibility rapid free CBP base formation Cyclobenzaprine HCl pKa = 9.7 Dipotassium phosphate pKa = 12.4 Oral cavity pH = 6.6 - 7.5 Eutectic Free particle contact between CBP.HCl with K 2 HPO 4 DE
Slide 41: Advantage of the Eutectic formation as a powerful Drug Delivery System
Redox ©2024 Advantage of the Eutectic formation as a powerful Drug Delivery System The knowledge of drug – excipient compatibility is vital in the pharmaceutical industry to avoid costly material wastage and time delays Tablet SL • Stability of CBP HCl • Protection from basic excipient • Fast Dissol
Slide 42: Patents related to eutectic CBP HCl + D mannitol
Redox ©2024 Patents related to eutectic CBP HCl + D mannitol 42 • The United States Patent and Trademark Office (USPTO) issued United States Patent No. 9636408 in May 2017, • Patent No. 9956188 in May 2018, • Patent No. 10117936 in November 2018, • Patent No. 10,357,465 in July 2019, some others
Slide 43: Example of Benefits from closely working together
Redox ©2024 Example of Benefits from closely working together 43 Research Development Clinical - stage biopharmaceutic al New Drug Product
Slide 45: Contributors to the Project
Redox ©2024 Contributors to the Project 45 REDOX – Monza - Italy P. Colombo M. Calvi M. Chirico APR Pharmaceutical – Balerna - Switzerland G. Reiner R. Marelli V. Reiner TONIX Pharmaceuticals – New York - USA S. Lederman S. Fogarty B. Daugherty M. Edgar

Tonix Pharmaceuticals Holding — 11th Global Conference on Pharmaceutics and Novel Drug Delivery Systems (PDDS) 2024 on 6ix

Tonix Pharmaceuticals — 11th Global Conference on Pharmaceutics and Novel Drug Delivery Systems (PDDS) 2024

Slide 1: Mannitol as a eutectic forming agent for improved sublingual delivery of Cyclobenzaprine HCl

Slide 2: Disclosures

Slide 3: Content

Slide 4: Compatibility strategy excipient impact

Slide 5: Thermodynamic parameters in API-Excipient interaction

Slide 6: Main Interaction and Physico-chemical Impact on API

Slide 7: Drug Excipient Compatibility - Experimental Design

Slide 8: Analytical Methods for drug-excipient compatibility assessment

Slide 9: Drug-excipient compatibility screening: thermoanalytical and spectroscopic techniques

Slide 10: Investigation by Thermal Analysis (DSC)

Slide 11: Eutectic formation during interaction

Slide 12: Case Study: compatibility investigation in sublingual formulation TNX-102 SL

Slide 13: Formulation development of TNX-SL tablet - trial n°1

Slide 14: Crystal Structure of Cyclobenzaprine.HCl

Slide 15: Physical Properties of Cyclobenzaprine HCl

Slide 16: D-mannitol Polymorphic Forms

Slide 17: D-mannitol X ray comparison between the polymorphic forms

Slide 18: D-mannitol crystallization and polymorphic transition

Slide 19: Compatibility procedure

Slide 20: DSC Compatibility Results - mechanical mixtures

Slide 21: Results of Compatibility Screening Cyclobenzaprine HCl with each excipient by DSC

Slide 22: Eutectic formation between Cyclobenzaprine HCl and D-mannitol beta form

Slide 23: Phase Diagram Cyclobenzaprine HCl - D-mannitol (beta form)

Slide 24: Phase Diagram by Melting Enthalpy of the Eutectic

Slide 25: Eutectic present in the formulation

Slide 26: XRPD of CBP HCl:D-mannitol mixtures

Slide 27: Compatibility by Wet Granulation

Slide 28: Eutectic Morphology by SEM

Slide 29: C NMR on D-mannitol alone and in eutectic with Cyclobenzaprine HCl

Slide 30: Screening by spray dry process to reduce eutectic particle size

Slide 31: Cyclobenzaprine HCl : D mannitol delta form

Slide 32: Phase Diagram Cyclobenzaprine HCl : D-mannitol (delta form)

Slide 33: Comparison of Phase Diagrams (beta vs. delta)

Slide 34: Morphology of Eutectics by SEM (beta vs delta)

Slide 35: Intrinsic Dissolution Rate (IDR)

Slide 36: Stability on the time of the two Eutectics

Slide 37: Eutectic stability in relation to the process

Slide 38: Interaction of the eutectic with Dipotassium phosphate

Slide 39: Proprietary Cyclobenzaprine HCl Eutectic stabilizes Transmucosal Sublingual Tablet Formulation

Slide 40: Influence of mouth pH on SL tablet dissolution

Slide 41: Advantage of the Eutectic formation as a powerful Drug Delivery System

Slide 42: Patents related to eutectic CBP HCl + D mannitol

Slide 43: Example of Benefits from closely working together

Slide 44: Chemico-physic Analyses

Slide 45: Contributors to the Project

Slide 46: Thanks for your attention