challenges and opportunities of development of salts of ......case study 1: disproportionation is...

Challenges and Opportunities of Development of Salts

of Weak Bases

Anand Sistla, PhD

(Suman Luthra, PhD)

September 10, 2018

Drug Delivery and Formulation Summit, San Francisco, CA

Phase 1 Phase 2PreclinicalLead Optimization LD

Influence

Chemistry

Formulate for Exposure

Formulate for Patients

“the estimated average pre-tax industry cost per new prescription drug approval (inclusive of

failures and capital costs) is $2.5 billion”- TUFTS 2014 SDD study

Fail Smart and Fail Early!

Reduce Attrition In

The Earliest

Stages Of Discovery

Select the right Form

and Formulation

About 40% of marketed drugs are

practically insoluble (<0.1mg/mL)

Ta

ka

gi,

Mo

lPh

arm

3:

2006

Enabling Technologies

Pfizer Confidential │ 3

Technology Solubility

Increase

Considerations

Nanomilling 1X Increase dissolution rate

Amorphous Polymer

Dispersions

5-100X May require high polymer content to sustain

in vivo

Salt/ cocrystals 5-1000X May not be sustained as API supersaturation

and precipitation can occur

SEDDS/ sSEDDS 10-1000X Risk of precipitation upon dilution, limited to

logP>4

Cosolvent 10-1000X Risk of precipitation upon dilution/limited for

safety studies

Outline

Why salts?

How is the Form selection done in current development process?

Do you consider salt disproportionation/ dissociation and when?


Why salts: Revision of what we already know…..

Bioperformance

Manufacturability

Stability/ Quality


• Increase in dissolution rate → Improve Cmax

• For poor crystallizers→ may improve AUC

• Better stability for strong/ more reactive bases

• Optimize process chemistry, ease of isolation and achieve

high purity

• Improve crystallinity, reduce hygroscopicity

• Optimize flow/ mechanical properties/ particle size/ habit

• Polymorphism http://dx.doi.org/1

0.1016/j.xphs.2017

.01.023

~50% approved API are

Salts

Trends in the Industry


Med. Chem. Commun., 2011, 2, 91–105

Salt selection 1.0


Tier 1: Candidate compliance for manufacturability:

Crystallinity, Melting point, hygroscopicity, solid

state stability

Tier 2: Solubility, intrinsic dissolution rate→

Improve oral BA

pKa = 11.8

Higher salt

solubility →

Higher exposure

in ratsFree base MP =

74.7°C

Maleate salt MP

= 163°C

Seo et al, 2015, Drug Design, Development and Therapy, v9 3961–3968

Serajuddin, IJP 337,

2007, 210

Reactive Engagement after Form Selection

• pKa= 3.8

• Wet granulation

• Tablet hardness

increased➔

Disintegration

times increased

• Citric acid addeddoi:10.1016/j.ijpharm.2004.01.042


• pKa = 6.3

• Salt selected to

improve MP and

dissolution rate

• Salt → Free base

in Tablets

• Free base was

volatile → Loss in

potencyIJP 337 (2007) 210–218

• pKa = 6.8

• < 1w at 40◦C/ 75%

RH, >20% reduction

in extent of

dissolution at 60

min.

• Mesylic acid formed

a complex with

Croscarmellose NaRohrs, Pharm. Res. 16, 1999, 1850-1856

• pKa = 5.1- 5.5

• HCl selected to

improve solubility

• IR film coated

tablets showed

lower oral BA in

clinical study in

patients with 1H

pump inhibitors

Unger, N. Engl. J. Med. 2009, 361, 942

S

NH

N

NNH

NH

NOO

OCH4O3S

N

S

O

F

O

O

HCl

9

Let’s think it through!!

pH – Solubility of Weak Bases; Solution Chemistry

• At pH= pHmax, salt (BHA) and free form (B)

are in equilibrium with saturated solution

• At pH > pHmax free form is stable

• At pH < pH max, salt is stable

Pfizer Confidential │ 10Solubility of Pharmaceuticals and Their Salts As a Function of pH dx.doi.org/10.1021/ie302064h | Ind. Eng. Chem. Res. 2013, 52, 2721−2731

pHmax

Lower pKa →lower pHmax

More soluble salts → lower

pHmax

Lower intrinsic

solubility→lower pHmax

pH

[so

lub

ilit

y]𝑝𝐻𝑚𝑎𝑥 = 𝑝𝐾𝑎 +𝑆𝑜

𝐾𝑠𝑝

Mechanistic Understanding Of API Phase Transformation In

solid state in DP

Monolayer

adsorption

Solid

Solution

Formation

Crystalline API Form

(salt/ cocrystal/ Hydrate/

Solvate) with defects

RH/ T

This adsorbed water either

“dissolves” the components and/ or

“enhances the mobility” of surface

species.

Assumption: Solution mediated

acid/ base chemistry occurs in this

adsorbed layer of water. Once

initiated at the activated sites,

reaction continues in the bulk

In presence of basic excipients,

microenvironment pH>pHmax ➔

Salt disproportionation is favored

• pKa

• Free base solubility

• Salt solubility

• Formulation composition

• T, RH

• Particle Size

Factors

Common Perpetrators in IR tablet formulations

Lubricants

• Mg Stearate

• Mg Stearyl Fumarate

Disintegrants

• Crosscarmellose Sodium

• Sodium starch Glycolate

pKa = 5.6

Free base S = 0.001mg/

mL

HCl salt solubility

= 0.4mg/m

L

pHmax ~ 3.0

PharmRes 2013: 30, 1626

Case study 1: Impact of pKa and pH max

• All of the salts (5%A) compressed as

standard IR formulations

– MCC, Lactose Monohydrate/ Dicalcium

Phosphate→ Fillers

– Magnesium Stearate→ Lubricant (1%)

– Explotab- Disintegrant (3%)


Name MW pKa

(UV)

∆pKa

Methane

sulfonic acid

pKa = -1.9

Free Base

Solubility

(mg/mL)

Mesylate salt

Solubility

(mg/mL)

pH Max

PF- Test 439 4.0 5.9 0.49 423.7 1.1

Ziprasidone 413 6.0 7.9 0.00025 0.9 2.4

Doxazosin 451 6.9 8.8 0.02 3.0 4.7

Sertraline 306 9.0 10.9 0.0003 8.5 4.5

Placebo BlendMicroenvironnement

pH by DRS(Hancock PharmRes 2006)

MCC: Lactose 5.0

MCC: DCP 4.4

PF-Test and

Ziprasidone

Mesylate salts

should

disproportionate

Microenvironment pH > pHmax

Luthra, AAPS NERDG Apr 2016

Case study 1: Disproportionation is instant in solution state:

at pH > pHmax

• Doxazosin Mesylate slurry in water ➔ No disproportionation observed.

• As pH increased to 2 units above pHmax (~4.7), significant conversion to amorphous form observed

instantaneously (orthogonal measurement via in-situ Raman as well).


Anhydrous Form B

In Water = Anhydrous Form B

Monohydrate Form F

In Buffer =Amorphous/poorly crystalline


Case study 1: Dispersive Raman Spectroscopy on tablets

• ~4-6% water adsorbed @ 30-40°C

• All samples were observed to be physically stable in refrigerated conditions.

• PF-test, the salt with lowest pH max showed disproportionation in IR compacts except in MCC: DCP @ 40°C/ 50%RH

• None of the other salts showed physical instability including Ziprasidone!!


IR

Formulations

1 Week 2 Week 4 Week 5 Week

40°C/50% 40°C/75% 30°C/75% 40°C/50% 40°C/75% 30°C/75% 40°C/50% 40°C/75% 30°C/75% 2-8°C

Doxazosin w/ MCC:Lactose N/A N/A N/A No No No No No No N.D

PF-Test w/ MCC: Lactose Yes Yes Possible Yes Yes Yes Yes Yes Yes No

Sertraline w/ MCC:Lactose N/A N/A N/A No No No No No No N.D

Ziprasidone w/ MCC: Lactose N/A N/A N/A No No No No No No N.D

Ziprasidone w/ MCC:DCP N/A N/A N/A No No No No No No N.D

PF- Test w/ MCC: DCP N/A Yes Possible No Yes Yes No Yes Yes No

Sertraline w/ MCC:DCP N/A N/A N/A No No No No No No N.D

Doxazosin w/ MCC: DCP N/A N/A N/A No No No No No No N.D


Microenvironment pH can influence salt disproportionation at high RH

Case study 2: Impact of polymorphic form

• 3 Forms of Miconazole Mesylate investigated

• Binary mixtures with TsPd (Trisodium phosphate dodecahydrate) or CCS (Croscarmellose Na)


pka = 6.7Solid Form of MM Solubility of free

base mg/mL

Thermodynamic Kinetics Calculated pHmax Solid form after 48

hr

AMO 9.98E-04 - 1125 ± 25 mg/ml 0.65 ± 0.01 Dihydrate

AH 9.98E-04 - 115 ± 10 mg/ml 1.64 ± 0.06 Dihydrate

DH 9.98E-04 48 ± 1 mg/ml 50 ± 2 mg/ml 2.02 ± 0.01 Dihydrate

Patel, GRC 2017, manuscript submitted to MolPharm

Case study 2: Impact of polymorphic form

• Rate and extent of salt disproportionation for different solid forms of MM is significantly different.

• AMO and AH form of the drug were found to be susceptible to disproportionation, while the DH form of MM

was resistant over the time period studied.

• AMO and AH forms also convert to DH.


CCSTsPd


Case study# 2: Polymorphic Form

CCS pH TSPd pH

pKa MCZ

• Extent of disproportionation for AMO was

about six times higher in presence of TSPd as

compared to CCS.

• Similarly, the amount of disproportionation for

AH was also higher (~three times) with TSPd

as compared to CCS.

• Competitive kinetics observed between

disproportionation and hydrate formation.

• Lack of detectable disproportionation of DH

cannot be explained based on consideration of

pHmax values


An Interesting Observation: Absence of Salt Bridge


• Molecule does not directly form a salt bridge with the mesylate ion.

• Molecule forms a hydrogen bond with a water molecule, which forms a second hydrogen bond with

another water molecule and this water molecule then forms a hydrogen bond with mesylate ion.

• Hypothesis: Hydrogen bonding network is shielding the salt bridge and inhibiting the proton transfer

needed for salt disproportionation to occur?

Miconazole

Mesylate Dihydrate


Cast Study #3: Impact of Buffer Capacity and acidic/ neutral excipients

• F1- Standard IR formulation with

Explotab as disintegrant and

Magnesium Stearate as lubricant

• F2- Modified IR formulation with

low pH Explotab as disintegrant

and Stearic acid as lubricant


S

N

N2

H pKa

Salt

solubility

mg/mL

Free Base

solubility

mg/mL

pH Max

HCl Salt 5.1 286 0.34 2.2

Oxalate salt 5.1 60 0.34 2.9

Oxalate Salt

HCl Salt

Neel Shah, Sweta Modi, Heather Frericks, Suman

Luthra:Buffer capacity:

HCl salt> Oxalate salt

Summary of Salt Disproportionation Risks

• Opportunities: Numerous advantages associated with making a salt of an ionizable compound.

Salt formation generally yields enhanced dissolution rate and solubility and, potentially oral

BA. Salts also can improve physicochemical properties of drug substances such as chemical

stability, manufacturability, melting point, moisture sorption, hydrate or polymorph landscape,

etc…

• Considerations:

– Only select the salt form if needed for long term development

– Consider long-term physical and chemical stability in presence of excipients and processing

and storage conditions over a 2-year period.

• Microenvironmental pH (excipients and impurities), pH of maximum solubility of salt

• Crystal structure of the salt

• Buffer capacity of salt and excipients


Salt selection 2.0

1

• Measured pKa of free form

• Candidate compliance for manufacturability: Crystallinity, Melting point >125°C, hygroscopicity, solid state chemical stability

2

• Thermodynamic solubility

• pHmax

3

Solid state instability risk in presence of common basic excipientsAssessment of supersaturation/ precipitation potential


Acknowledgements

• Sheri Shamblin

• Joe Krzyzaniak

• Sweta Modi

• Heather Frericks Schmidt

• Albert Chen

• Neel Shah

• Prof. Lynne Taylor (Purdue University)

• Mitul Patel (Purdue University)


Summary

• Salts of weak bases may promote dissolution and supersaturation resulting in

enhanced oral bioavailability compared to free forms.

• Due to manufacturing processes and formulation with basic excipients, risk of

disproportionation should be actively evaluated for the design of robust solid dosage

forms of weak bases.

• Solubility of the salt and pHmax are good starting points for evaluation of risk of salt

disproportionation in drug product and in-vivo.

• Formulations as free base using either particle size reduction or as an amorphous

drug-polymer dispersions are recommended for increasing oral absorption for low

solubility weak bases.


25

Thank you for your attention!

Dr Steve Carney, [email protected]

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