Poorly soluble drugs are the nemesis of formulation development scientists. Bruce Rehlaender the big issues and points out some approaches for dealing with these drugs and improving their bioavailability.
“Emulsion of emulsion”, “double or triple emulsion”
Dispersed phase contain smaller droplets that have the same composition as the external phase.
Liquid film which separate the liquid phases acts as a thin semi permeable film through which solute must diffuse in order to travel from one phase to another – “Liquid Membrane System”
Two types: -
Oil-in-water-in-oil (O/W/O) emulsion system.
Water-in-oil-in-water (W/O/W) emulsion system.
Superdisintegrants in Orally Administered Products of Pharmaceuticals A Reviewijtsrd
Superdisintegrants are developed to improve the palatability in orally administered products and to advancing the development of various formulations with increase performance and acceptability. Superdisintegrants are used to revise the potency of solid dosage form .This is accomplish by decreasing the disintegration time which in turn improvement the drug dissolution rate. Diverse categories of Superdisintegrants such as synthetic, semi synthetic, natural and cross processed blend etc. The present study comprises the various kinds of Superdisintegrants which are being used in formulations to provide the safer effective drug delivery with patient’s compliance. Snehal N. Dhoot | Sharda P. Shahane | Kiran. P. Gaikwad | Leena P. Joge | Jaya P. Ambhore "Superdisintegrants in Orally Administered Products of Pharmaceuticals: A Review" Published in International Journal of Trend in Scientific Research and Development (ijtsrd), ISSN: 2456-6470, Volume-6 | Issue-4 , June 2022, URL: https://www.ijtsrd.com/papers/ijtsrd50282.pdf Paper URL: https://www.ijtsrd.com/pharmacy/pharmaceutics/50282/superdisintegrants-in-orally-administered-products-of-pharmaceuticals-a-review/snehal-n-dhoot
“Emulsion of emulsion”, “double or triple emulsion”
Dispersed phase contain smaller droplets that have the same composition as the external phase.
Liquid film which separate the liquid phases acts as a thin semi permeable film through which solute must diffuse in order to travel from one phase to another – “Liquid Membrane System”
Two types: -
Oil-in-water-in-oil (O/W/O) emulsion system.
Water-in-oil-in-water (W/O/W) emulsion system.
Superdisintegrants in Orally Administered Products of Pharmaceuticals A Reviewijtsrd
Superdisintegrants are developed to improve the palatability in orally administered products and to advancing the development of various formulations with increase performance and acceptability. Superdisintegrants are used to revise the potency of solid dosage form .This is accomplish by decreasing the disintegration time which in turn improvement the drug dissolution rate. Diverse categories of Superdisintegrants such as synthetic, semi synthetic, natural and cross processed blend etc. The present study comprises the various kinds of Superdisintegrants which are being used in formulations to provide the safer effective drug delivery with patient’s compliance. Snehal N. Dhoot | Sharda P. Shahane | Kiran. P. Gaikwad | Leena P. Joge | Jaya P. Ambhore "Superdisintegrants in Orally Administered Products of Pharmaceuticals: A Review" Published in International Journal of Trend in Scientific Research and Development (ijtsrd), ISSN: 2456-6470, Volume-6 | Issue-4 , June 2022, URL: https://www.ijtsrd.com/papers/ijtsrd50282.pdf Paper URL: https://www.ijtsrd.com/pharmacy/pharmaceutics/50282/superdisintegrants-in-orally-administered-products-of-pharmaceuticals-a-review/snehal-n-dhoot
Phase solubility analysis and pH solubility profileMohit Angolkar
A Brief presentation on the topic- phase solubility analysis and pH solubility profile, which covers the following aspects:
- Solubility introduction
- importance of solubility
- factors influencing solubility
- Phase solubility analysis introduction
- method of analysis
- purification technique
- introduction to pH solubility profile.
Dissolution : Official and Non official methods, Alternative methods of dissolution testing and transport models, Drug release testing, Invitro drug release testing
Formulation development of insoluble drugs has always been a challenge in pharmaceutical development. This presentation reviews some current options to old problem.
Phase solubility analysis and pH solubility profileMohit Angolkar
A Brief presentation on the topic- phase solubility analysis and pH solubility profile, which covers the following aspects:
- Solubility introduction
- importance of solubility
- factors influencing solubility
- Phase solubility analysis introduction
- method of analysis
- purification technique
- introduction to pH solubility profile.
Dissolution : Official and Non official methods, Alternative methods of dissolution testing and transport models, Drug release testing, Invitro drug release testing
Formulation development of insoluble drugs has always been a challenge in pharmaceutical development. This presentation reviews some current options to old problem.
A Nanosuspension is a submicron colloidal dispersion of drug particles. A pharmaceutical nanosuspension is defined as very finely colloid, Biphasic, dispersed, solid drug particles in an aqeous vehicle , size below 1µm ,without any matrix material, stabilized by surfactants and polymers , prepared by suitable methods for Drug Delivery applications, through various routes of administration like oral ,topical ,parenteral ,ocular and pulmanary routes.
Dissolution is mass transfer process.
Dissolution is mainly depend on aqueous solubility of drug.
It is process in which solid mass transfer in liquid medium.
Dissolution based on four process – 1. wetting 2. solubility 3. Swelling 4. diffusion.
Particle size, shape, surface area is important factor can affect the rate of dissolution of drug.
The aqueous solubility is increases, increases rate of dissolution drug
Bio pharmaceutical classification System [BCS]Sagar Savale
The Biopharmaceutical Classification System was first developed by in 1995, by Amidon et al & his colleagues.
Definition:
“The Biopharmaceutical Classification System is a scientific framework for classifying a drug substance based on its aqueous solubility & intestinal permeability & dissolution rate”.
To saved time fast screening is required so drug substances are classified on basis of solubility and permeability. This classification is called Biopharmaceutical Classification System
What’s a suspension ?
Suspension Requirements?
Why a suspension?
Stability;
HOW TO MAKE A FINE POWDER? (10-50 MICRON)
Fluid Energy
Preparing Flocculated suspensions
Formulation considerations for orally administered suspension:
Rheology
Rheology for Pharmacists
Excipients used in the formulation of suspensions for oral administration:
Excipients used in the formulation of suspensions for oral administration:
Some subdosage forms of suspensions
Extemporaneous Prepration:
This slide contains the preformulation studies.It contains the various physicochemical properties that must be undergo to formulate the better absorption and stabiity of the different type of dosage form.This is ultimately used for the B Pharmacy final year students.Download the colourful ppt and enjoy the experience.
A) Carrier linked prodrugs and B) Bioprecursors
A) Carrier linked prodrugs- active drug linked to a carrier group
Carrier group- should be labile, non-toxic, biologically inactive
Further divided to bipartate, tripartate and mutual prodrugs
1. Bipartate- prodrug with carrier
2. Tripartate- carrier + linker + prodrug
3. Mutual prodrug- synergistic drugs connected to each other
Liposomes-Classification, methods of preparation and application Vijay Hemmadi
liposome preparation and application
A liposome is a tiny bubble (vesicle), made out of the same material as a cell membrane. Liposomes can be filled with drugs, and used to deliver drugs for cancer and other diseases. Membranes are usually made of phospholipids, which are molecules that have a head group and a tail group
Sr no Contents
1 Introduction
2 Advantages and disadvantages
3 Types of nanoparticle
4 Classification of Nanoparticle
5 Polymers used in nanoparticles
6 Method of preparation
7 Evaluation of nanoparticles
8 Application of nanoparticles
9 References
Nanoparticles is derived from the Greek word Nano means extremely small.
Nanoparticles are sub Nano sized colloidal drug delivery systems .
Particle size ranges from 10-1000 nm in diameter .
They are made up of natural, synthetic or semi synthetic polymers carrying drugs or proteinaceous substances, i.e. antigen(s) .
Drugs are entrapped either in the polymer matrix as a particulates or solid solutions or may be bound to particle surface by physical adsorption or by chemical reaction.
Drug can be added during preparation of nanoparticles or to the previously prepared nanoparticles
Nanoparticles can act as controlled release system depending on their polymeric composition.
As a targeted drug carrier nanoparticles reduce drug toxicity
Less amount of dose required.
They enhance aqueous solubility of poorly soluble drug therefore increase its bioavailability, therapeutic efficacy and Reduces side effects.
Nanoparticles can be administer by various routes including oral, nasal, parenteral, intra-ocular etc.
A) AMPHIPHILIC MACROMOLECULE CROSS-LINKING
B) Polymerization method
C)Polymer precipitation method
Heat cross-linking
Chemical cross-linking
Emulsion chemical dehydration
By Crosslinking in W/O Emulsion
PH-induced aggregation
Counter ion induced aggregation
Emulsion polymerization a)Micellar nucleation and polymerization b)Homogenous nucleation and polymerization)
Dispersion polymerization
Interfacial polymerization
Emulsion solvent evaporation method
Double emulsion and evaporation method
Solvent displacement
Salting out
Nanoprecipitation
Contact lens care and maintenance
RGP care
Soft Contact lens care
Silicon Hydrogel Care
Contact Lens Disinfection
Thermal disinfection
Chemical Disinfection
Oxidative chemical disinfection
Similar to Formulation Development of Poorly Soluble Drugs (20)
Moving From Paper-Based Systems to Electronic Batch Records - InstantGMP™InstantGMP™
Technology is constantly evolving around us, and yet many manufacturers continue using paper-based systems to manage and record their activities while manufacturing. In recent times, many of these manufacturers, especially in pharmaceuticals and biotech, are making the move to a Manufacturing Execution System (MES) and Electronic Batch Records (EBR).
InstantGMP MD is the latest version of InstantGMP's good manufacturing practices software. MD brings manufacturers of medical devices into cGMP compliance by coming fully validated and compliant with Part 820.
InstantGMP Compliance Series - Facility DesignInstantGMP™
The design of facilities used in the manufacturing of dietary supplements must meet strict requirements for preventing mix-ups and cross contamination. This presentation describes how this can be done.
InstantGMP Compliance Series - EquipmentInstantGMP™
Equipment used in producing dietary supplements fall under Good Manufacturing Practices. This presentation offers guidance on how to keep equipment in compliance.
InstantGMP Compliance Series - Managing Deviations for Improved ComplianceInstantGMP™
Any time a deviation is made from the process in the batch production record, it has to be recorded, investigated and disposition. This presentation provides details on how this is done.
InstantGMP Compliance Series - Improving Quality through In-Process ControlInstantGMP™
In-Process controls are needed at each step of a manufacturing procedure where the control of a critical process can affect the quality of the final product. This presentation explains how to set and use in-process controls.
InstantGMP Compliance Series - Improving SpecificationsInstantGMP™
The FDA requires specifications for identity, strength, purity and composition for dietary supplement products. This presentation explains how to meet these GMP requirements.
InstantGMP Compliance Series - Improving Batch Production RecordsInstantGMP™
Batch record violations were frequently cited during FDA inspections of dietary supplement manufacturers. This presentation provides some guidance on what is needed for batch records to be in compliance with GMPs.
Instant GMP Compliance Series -Better Compliance through Master Manufacturing...InstantGMP™
FDA inspections are increasing every year and they have published the results on their website. 50% of dietary supplement manufacturers are not in GMP compliance and 1 in 4 dietary supplement companies have received a warning letter which could result in a significant enforcement action such as halting production and distribution. Many of these producers received citation because they were not using Master Manufacturing Records.
Instant GMP Compliance Series - Improving DocumentationInstantGMP™
The FDA enforces the Dietary Supplement Health and Education Act (DSHEA) law by inspecting dietary supplement manufacturers, packagers, labelers and holders for Current Good Manufacturing Practices (cGMPs) compliance. One of the main issues they found was the lack of proper documentation. This presentation provides an overview of the documentation that is needed for cGMP compliance.
Instant GMP Compliance Series for Dietary Supplements – Cost of ComplianceInstantGMP™
This presentation is one in a series of presentations that focus on good manufacturing practices and cGMP compliance for dietary supplements manufacturing. It’s brought to you by the quality and manufacturing experts at InstantGMP in the hope that it will help you avoid any cGMP compliance issues in your shop.
Instant GMP Compliance Series for Dietary Supplements – IntroductionInstantGMP™
Since 2010, the FDA has stepped up their inspections of dietary supplement manufacturers. At least 1 in 4 of those companies inspected received a Warning Letter to improve cGMP compliance or suffer regulatory action. This prompted us to prepare a series of presentations that will focus on good manufacturing practices and cGMP compliance for dietary supplements manufacturing. It’s brought to you by the quality and manufacturing experts at InstantGMP in the hope that it will help you avoid any cGMP compliance issues in your shop.
Any company involved in the dietary supplement business has to establish and to follow GMPs to ensure that packaging and labeling is done as specified in the master manufacturing record and to ensure the quality of the product that reaches the market. The presentation provides an overview of these requirements.
GMP Manufacturing for Worldwide Clinical Trials InstantGMP™
This presentation describes the complex process of manufacturing clinical trial materials using examples from the InstantGMP manufacturing execution system. InstantGMP is an electronic batch record system for small pharmaceutical operations and is ideal for manufacturing CTM or tracking inventory worldwide.
1. Poorly Soluble Drugs
Trials and Tribulations of the Modern Formulator
Bruce Rehlaender, Ph.D.
Principal, Formulation Development
PharmaDirections, Inc.
1
2. The Problem of Insolubility
• Med Chemists are obsessed with affinity
and selectivity
2
3. The Problem of Insolubility
• Med Chemists are obsessed with affinity
and selectivity
• Solubility can get left by the wayside
3
4. The Problem of Insolubility
• Med Chemists are obsessed with affinity
and selectivity
• Solubility can get left by the wayside
• General tendency is that new drugs are
becoming more insoluble
4
5. The Problem of Insolubility
• Med Chemists are obsessed with affinity
and selectivity
• Solubility can get left by the wayside
• General tendency is that new drugs are
becoming more insoluble
• And Formulators are
going crazier
5
6. Classes of Problem Children
Non-ionized weak Halogenated
acids or weak bases molecules
Lipophilic Brick dust
molecules
Amphiphilic
molecules Macromolecules
6
7. Two Big Issues with Insolubility:
• Cannot give particles IV
emboli
• Poor Bioavailability ng/mL
100
IV
50
Oral
0
0 3 6 9 12
hours
7
8. Bioavailability Solutions
• Make drug particles
smaller
– ↑ Dissolution rate (kinetic)
*
– ↑ Solubility (thermodynamic)
• You can go to extremes and…
8
13. pH Adjustment
• Most drugs are weak acids or weak bases
• Solubility depends on ionization state
Solubility of Weak Base Solubility of Weak Acid
100 100
10 10
Solubility
Solubility
1 1
pKa pKa
0.1 0.1
0.01 0.01
0.001 0.001
pH pH
• Can get large solubility increase if pH still
reasonable 13
14. pH Adjustment
What pH is acceptable for injection?
• It depends…..
– Route of administration (central vein IV,
peripheral vein IV, SubQ, IM)
– Rate and duration of administration
– Buffer capacity of the formulation (D5W is in
spec at pH 2.5 due to lack of buffering)
– Indication (routine vs. critical, acute vs.
chronic)
• Problem is that you need buffer to assure
solubility, but buffering decreases range
14
15. Pop Quiz
Which of these excipients are allowed for use
in injectable products?
– Polyethylene glycol?
– Ethanol?
– Bile salts?
– N-methyl-pyrrolidone (NMP)?
– Dimethyl-acetamide (DMA)?
– Polysorbates (Tweens)?
• All of the above are used in approved injectable
products
15
16. Co-Solvent Formulations
• Adding a water-miscible solvent can
reduce polarity and increase solubility
• Most typical solvents are propylene
glycol, low MW PEGs, and ethanol.
– Problem: Typical Solubility Curve
you need a lot
– Can sometimes get
Solubility
formulation that is
metastable upon dilution 0 20 40 60
% Co-Solvent
80 100
in aqueous
16
17. Co-Solvent Formulations
How much solvent is allowed?
• It depends…..
– Route of administration (central vein IV,
peripheral vein IV, SubQ, IM)
– Rate and duration of administration
– Indication (routine vs. critical, acute vs.
chronic)
• These formulations are very hypertonic, so
best for IV or dilute-for-use
• Example: several formulations with 40%
PG and 10% ethanol for IV and IM
17
18. Complexes (Cyclodextrins)
• Cyclodextrins are “basket-like” molecules
with a hydrophobic pocket and hydrophilic
exterior
• Hydroxypropyl-β-CD and sulfobutyl ether- β-
CD used for injectables
• Need high concentration (>10%) since level
needs to be stoichiometric with drug
• Quite safe. Only significant issue is some
nephrotoxicity
• Licensing was a big issue in past
18
20. Micelles and Microemulsions
• Micelles are aggregates of surfactant
molecules that can solubilize drugs.
• Typically used surfactants are:
– Polysorbates (PEGylated sorbitan fatty acid esters)
– Cremophor (PEGylated castor oil)
– Pluronic F68 (PEG/PPG block copolymer)
– Solutol (PEGylated hydroxystearate)
• All can cause anaphylactic reactions
• Example: Taxol formulated in pure surfactant.
Diluted to metastable dispersion prior to infusing
20
22. Emulsions
• In contrast to micelles/microemulsions,
emulsions are thermodynamically unstable
• Prepared with high pressure homogenizer
• Oil droplet size typically >0.2 µm, so must be
heat (or radiation) sterilized
• Oil droplets similar to chylomicrons, so are
very safe
• Phospholipids used as emulsifier. Non-ionics
(Tweens, etc.) can be used for non-sterile
products but cannot take heat
22
24. Liposomes
• Liposomes are small vesicles composed of
phospholipid bilayers
• Liposomes are also unstable and are
typically quite fussy and expensive
• Like emulsions, liposomes are very non-
toxic
• Unlike emulsions, liposomes can be sterile
filtered and lyophilized
• Special process equipment is required
24
26. Summary
Approach + -
Tight range for comfort
Adjust pH Simple, few excipients
and stability
Toxicity, osmolarity,
Co-solvent Simple process
precipitation on dilution
Complexes Low toxicity, dilutable, High cost, process can
lyophilizable be moderately complex
Anaphylaxis and other
Micelles Simple process, dilutable
toxicity issues
Non-toxic, isotonic, Complex process,
Emulsion generally dilutable no filter sterilization
Non-toxic, isotonic, Cost, complex process,
Liposomes filterable, lyophilizable poor physical stability
26
27. Choosing a Formulation
Formulating poorly soluble drugs is like
voting….
There are seldom good options, just
least objectionable ones
27
28. Choosing a Formulation
What system is right for you?
• It depends…..
– What solubilizes your drug (first and foremost)
– Stability considerations
– Route, rate, and duration of administration
– Factors specific to disease state
– IP considerations and, of course, marketing
• Step 1: Cast a broad net to identify your
options
• Step 2: Choose your poison
28
29. The Dilemma of Druggability
Pharmacology Druggability
Receptor Affinity Solubility
very
Stability
Receptor Specificity
Disco
Hygroscopicity
Activity once bound Powder characteristics
(agonist or antagonist)
Polymorphism
Toxicity
Permeability/Absorption
Clearance/PK
The most active molecule isn’t always the best drug
29
Often the two are at odds with each other, and