Preformulation and Formulation Development

Preformulation and formulation development can deal with two challenges that might be considered as opposites:

·         Developing drugs with greater speed; and

·         Processes of drug development are growing more complex and time-consuming. From Lead to Clinical Trials

Let us imagine that, as a medicinal chemistry team, your lead has just been chosen. By outsourcing (drug discovery support) or in-house, you have got the materials to go through first toxicology and pharmacokinetic studies. Are you now ready to go to

clinical trials?

As a contract development organisation (CDO), Companies have seen several customers that have booked their clinical trials to a CRO (contract research organisation) and come to them to ask for some drug products to provide to the CRO. The step between the current Good Manufacturing Practices (cGMP) batch manufacturing of the active pharmaceutical ingredient (API) and the release for clinical trials, might be simple, but might be very complex also.

To address the question mark in Figure 1, consider preformulation and formulation development.

Preformulation

Preformulation is not only about stability and solubility data as shown in a lot of contract services supplier websites. Far from that, preformulation must be considered as an interface between the drug substance and the drug product.

According to the Product Quality Research Division of the US Food and Drug Administration (FDA), the goal of preformulation is to “investigate critical physicochemical factors which assure identity, purity of drug substances, formulatability, product performance and quality.”

Whatever the form may be, the end-use properties of the drug product are linked with:

·         Dose and release – what amount of the drug substance is needed in what time?;

·         Bioavailability and toxicity – drug performance level compared with side effects; and

·         Stability and shelf-life – to ensure quality and performance during storage.

Solubility determination, salt selection and pKa measurements are, of course, driven by dose. For instance, if the effective dose is 10mg and the drug solubility in water is 0.01mg/ml, it may be better to find a stable salt with a higher solubility than to inject one litre of solution.

Less known is the impact of crystal properties and polymorphism. If you have already experienced (or withstood) a polymorphic form appearing or disappearing, then you already know the major effect that crystal properties can have on solubilities, dissolution rate, toxicity, formulation process and so on. If not, what a lucky person you are! However, you must still be aware that the FDA recommends the characterisation of your drug substance by X- ray diffraction at the minimum, even in the pre-investigational new drug (IND) stage.

Particle size and surface area have an impact on dissolution rate. Usually, the higher the surface area, the higher the dissolution rate, but very fine particles can agglomerate, leading to caking and problems

during dispersion. By changing crystallization conditions on the drug substance, you may have a direct impact on solid handling during formulation step, solid handling needed both for oral forms (flowability) and parenteral (in the dosing hopper).  The effects of surface properties are less known, although they are of major importance for bioavailability. All interactions within the human body are driven by hydrophilicity and/or lipophilicity, depending on adsorption, cell absorption, membranes crossing, antibody interactions and so on. All the components of the ormulation are part of this game, but even in targeting delivery, the final step is the release of the active. The partition coefficient or surface tension for an oral form have to be taken into account.

A preformulation team needs experts in chemistry, analysis, chemical engineering and physical characterisations. A supplier in preformulation might be able to provide:

·         Physicochemical properties of the drug substance:

Ø      Solubility studies

Ø      Ssalt screening, pKa determination

Ø      Partition coefficient, hydrophilicity, lipophilicity

Ø      Crystallisation studies (impact on amorphous, particle shape, size and brittleness)

Ø      Polymorphism studies – identification, screening, relative stability (enantiotropy/ monotropy), process design and scale-up to ensure robustness of the obtained polymorphic form, dosage method of mixture;

·         Stability data:

Ø      Chemical stability, accelerated and stress studies

Ø      Thermal properties

Ø      Hygroscopicity (storage conditions)

Ø      Excipients and packaging compatibility studies; and

·         Early stage formulation:

Design composition and form according to specifications, dose and bioavailability. Depending on phase development, amount of drug available, the above preformulation studies will be adapted to obtain the right level of information according to the risk that the customer is ready to take.

In early stage, formulation might be the simplest option. However, even for the simplest  forms like solution and capsules, the right levels of stability data, analytical validation and standard operating procedure are needed for the release of the drug product for clinical trails. Fortunately, drugs must not be delivered to humans without some controls.

Let us give an example of a cytotoxic anticancer drug. For an oral form, capsules will be prepared by direct mixing, if possible, or granulation, if needed. During preformulation studies, excipient compatibility studies will have been carried out to choose rapidly the right ones to ensure stability. Bulk density of the API will have been checked, otherwise, depending on the API batch scale, bulk density might change even by a factor of 100%, leading to a powder that will no longer fill your capsules with the same amount of API.

At a minimum, polymorph identification on several batches will have been carried out also, although you will experience great differences in solubility if new polymorphic forms appear.

 For a parenteral formulation, if solubility and stability are correct, you will try a solution, otherwise you will have to go to lyophilisation. Cryomicroscopy and thermal analyses will be very useful to design the formulation and the lyophilisation cycle. Holding time of the solution before repartition, filtration conditions, reconstitution time on the lyophilised product, purity and stability will be checked to ensure a procedure that can be used for the manufacturing of the drug product for clinical trials.

It has to be noted that, with the new European Directive (May 2004) for Clinical Trials, batch manufacturing now has to be performed under cGMP rules and released by a qualified person.

For all forms, stability data is needed both on the API and finished product to give a shelf life for the drug at a minimum equivalent to the duration of the clinical trials. A supplier in formulation development might be able to provide:

·         Expertise and equipment for:

Ø      Oral forms – powders, granules, capsules, tablets, suspensions, emulsions, syrup

Ø      Parenteral forms – solutions, lyophilisates, nanoparticules, fine emulsions

Ø      Inhalation forms such as dry powder inhalation

Ø      Topical forms – semi-solids;

·         Innovation and scale-up knowledge in drug  delivery design – microencapsulation, spray drying, spray cooling, controlled release, phase inversion temperature emulsions;

·         Analytical method validation and stability according to ICH guidelines;

·         Regulatory (FDA, EMEA directives for clinical trials); and

·         Project management in order to handle all the time, cost and regulatory constraints for different internal and external suppliers – development team, manufacturing team, packaging, labeling and final release of the drug product.

Methodology

As a conclusion, methodology to balance speed, on one hand, and a complex and time-consuming process, on the other hand, will be:

1. awareness – be aware, or work with a supplier who is aware, of all the traps that might occur during development and scale-up, be aware of changing regulatory constraints and of risks;

2. expertise in development with people able to solve the problems that will occur and who have already experienced and overcome such trouble- shooting; and

3. communication and transparency between all the players so that the customer might be able to make the best choices and the best compromises

Hydrodynamically Balanced Capsules

Hydrodynamically Balanced Capsules

Apart from HBS tablets many investigators also formulated HBS capsules. The pharmacokinetics of the new drug delivery system named Madopar HBS was developed, which was characterized by lower and delayed plasma peak concentrations but a longer-lasting concentration of L-DOPA and benserazide than standard Madopar. Therefore, this new controlled release system reduced the clinical fluctuations occurring in parkinsonian patients with "wearing-off" and "on-off" phenomena The drug is released and absorbed over a period of 4-5 h, thus maintaining substantial plasma concentrations for 6-8 h after dosing. The presence or absence of food in the stomach has no effect on the absorption of L-DOPA from Madopar HBS, but administration of antacids reduces the bioavailability. Thus, Madopar HBS showed improvement in the clinical condition by about 86% on average as compared with standard Madopar
Khar  formulated sustained-release floating capsules containing salbutamol sulfate, using different combinations of hydrocolloids of natural and semi-synthetic origin. The floating capsule formulated showed a Higuchian release profile, while the marketed product released only about 80% of the total dose in the stipulated 12 h in the dissolution medium. In vivo x-ray studies of the abdomen indicated a residence time up to 8-9 h in the stomach greater than for the non-floating capsule.

A bilayer floating dosage unit composed of HPMC was formulated by Oth et al. to achieve local delivery of misoprostol (a prostaglandin E1 analog) at the gastric mucosa level. The use of a large capsule increases the GRT, as it impedes passage through the pylorus opening. GS studies revealed the average GRT was199 ± 69 min after a single meal (breakfast) and 618 ± 208 min after a succession of meals.

Hydrodynamically Balanced Systems with Gas-Generating Agents

Buoyancy in tablets and capsules could be achieved by incorporating hydrophilic matrix or by incorporation of some inorganic salts that generate gas when in contact with the gastrointestinal fluids.

Baumgartner et al developed the floating matrix tablets with HPMC and by incorporating gas-generating agent together with microcrystalline cellulose in the formulation. The tablet composition and mechanical strength were retained and the floating characteristics as well the drug-release pattern were maintained by properly optimizing the formulation. The floating time was optimized with floating lag time of approximately 30 s and the duration of floating was more than 8 h. Radiological evidence suggests that, the formulated tablets did not adhere to the stomach mucus and that the mean GRT was 4 h.

Ichikawa et al.developed an oral floating dosage system, which generated carbon dioxide gas. The system was composed of sustained release pills as seeds and double layers on the sustained release pills. The inner layer comprised an effervescent layer containing both sodium bicarbonate and tartaric acid separated by an inert layer. The outer layer was a swellable membrane layer containing mainly polyvinyl acetate and purified shellac. When the system was immersed in water, it formed swollen pills like balloons with a density much lower than 1.0 g/cm ³ . The reaction was due to carbon dioxide gas generated by neutralization in the effervescent layer with the diffusion of water through the swellable membrane layer. The buoyancy lag time was approximately 10 min and 80% remained floating over a period of 5 h irrespective of pH and viscosity of the test medium. The release rate of the drug from the system depends on the sustained release characteristics of the system. 

Minitablets formulated by Rouge et al achieved buoyancy either by the swelling of the excipient or by incorporation of the gas-generating agent sodium bicarbonate. The buoyancy of the minitablets containing atenolol was greatly improved by adding gas-generating agent sodium bicarbonate to the floating layer as well as by a wet granulation. Atenolol minitablets containing 7% sodium bicarbonate and coated with Eudragit NE30D:RS 70:30 yielded satisfactory results regarding buoyancy and drug release rate for 6 h. 

A bilayer floating tablet for gastric retention with cisapride as a model drug was developed by Wei et al  Sodium bicarbonate was added to the floating layer. The tablet when immersed in simulated gastric fluid (SGF) expanded and rose to the surface and eventually the drug was found to release gradually. The in vitro drug release of this type of bilayer dosage was controlled by the amount of HPMC in the drug loading layer. Generally, more the HPMC, slower the drugs release. As cisapride has greater solubility in SGF than simulated intestinal fluid (SIF), itsin vitro drug dissolution is faster as compared with SIF.

Frances et al. formulated floating calcium alginate beads, designed to improve drug bioavailability from oral preparations compared with that from many commercially available and modified release products, have been investigated as a possible gastroretentive dosage form. They incorporated riboflavin as a model drug into the formula.

Reference:

http://www.sysrevpharm.org/article.asp?issn=0975-8453;year=2010;volume=1;issue=1;spage=33;epage=39;aulast=Sabale

Hydrodynamically Balanced Systems

Hydrodynamically Balanced Systems

Sheth and Tossounian developed an HBS system containing a homogeneous mixture of drug and the hydrocolloid in a capsule, which upon contact with gastric fluid acquired and maintained a bulk density of less than 1, thereby being buoyant on the gastric contents of stomach until all the drug was released. The HBS is the novel dosage form, which when in contact with gastric fluid and after dissolution of the outer exposed surface of the dosage form, forms a hydrated gel layer and maintains bulk density less than 1 g/cm ³ Thus, this system remains buoyant in the gastric fluid inside the stomach for 6 h. Conventional dosage form disintegrate completely within 60 min and are emptied totally from the stomach shortly afterward. This dosage form releases the drug through the hydrated layer by diffusion principle. This system is valuable for drugs, which are soluble at lower pH and have absorption window in the upper GIT. By varying the composition of the excipient between 20% and 75% w/w of one or more gel-forming hydrocolloids such as hydroxyethylcellulose, hydroxypropylcellulose, HPMC and sodium carboxymethylcellulose, the granules are prepared and compressed into tablets or encapsulated into capsules, which results in the desired release rate of the drug. This hydrated gel controls the rate of solvent penetration into the device and the rate of drug release from the device.

In the early 70's, Michaels first introduced floating drug delivery device with self-activated mechanism for retaining the device in the stomach, which released the drug under controlled osmotic pressure. The device was found to consist of two chambers, one for the drug reservoir and the other for the osmogen. In the stomach the gastric fluid dissolves the osmogen, which creates pressure on the drug reservoir compartment. This pressure tends to reduce the total volume of drug reservoir compartment, thereby leading to the continuous release of the drug material from the device. In another attempt, Michaels sustained the release of drug in stomach by incorporation of liquid such as ether in an inflatable chamber. In the gastric fluid, the chamber inflates and retains the drug reservoir in stomach. The drug solutes are continuously released from the reservoir into the gastric fluid. Harrigan ^[24] formulated a drug delivery device with a chamber, which contained vacuum or filled with air or harmless gas. This made the dosage form to float in gastric fluids. The fluids enter the microporous aperture, dissolve the drug and carry the drug solutes out of the drug delivery system for absorption.

Later, Mao et al. ^[25] prepared oral controlled-release system of metoprolol (M-HBS) with first-order in vitro release kinetics. The gamma scintigraphy (GS) study indicates that after oral ingestion, M-HBS was retained in human stomach for longer time (5-6 h) than the conventional metoprolol tablet (1-1.5 h). The values of t _max and C _max were 5.247 h and 125.1 ng/ml, respectively. Moreover, the fraction of the dose absorbed from M-HBS in vivo is well correlated with dissolution rate in vitro. 

Sawicki formulated 40 mg verapamil floating tablet, which had a C _max of 28.27 ng/ml, t _max 3.75 h and AUC 364.65 ng/ml h, whereas the conventional tablets have 33.07 ng/ml, 1.21 h and 224.22 ng/ ml h, respectively. Thus, the formulation had higher AUC and Ke, and therefore had a sustained release pattern.

A HBS-controlled drug delivery tablet of miocamycin was developed by Diao et al The GS study after oral ingestion showed that miocamycin HBS remained in human stomach for more than 7 h, which is much longer than the conventional tablet (3-4 h). The in vitrorelease characteristics showed first-order kinetics. The serum concentration time course of miocamycin HBS exhibited typical sustained release characteristics. 

Krogel et al.investigated the release behavior of the different devices as a function of HPMC viscosity grade, HPMC content, type of drug (chlorpheniramine maleate or ibuprofen), matrix weight, position of the matrix within the polymeric cylinder, addition of various fillers (lactose, dibasic calcium phosphate or microcrystalline cellulose) and agitation rate of the release medium. The drug release increased with a reduced HPMC viscosity grade, higher aqueous drug solubility, decreased HPMC content and increased surface area of the matrix. The release was fairly independent of the agitation rate, the position of the tablet within the polymeric cylinder and the length of the cylinder. With the pulsatile device, the lag time prior to the drug release could be controlled through the erosion rate of the matrix.

Wu et al. prepared a solid dispersion of nimodipine with poloxamer 188 and added excipients (HPMC and PEG 6000) to formulate floating-sustained release tablet. Increasing the HPMC content and decreasing PEG 6000 content led to decrease in nimodipine release in vitro. The optimized formulation showed gastric residence time (GRT) of 5 h under fed condition, while GRT was only 3 h under fasting condition. GRT of nimodipine conventional tablet under fed and fasting conditions was 3 and 2 h, respectively. Relative bioavailability of nimodipine floating tablet was 391.46% and GRT over twice that of nimodipine conventional tablet, which appeared to have prolonged GRT and improved bioavailability. Similarly, captopril floating tablets were prepared by Nur et al. using HPMC (4000 and 15,000 cps). With this the release profile of captopril from floating tablets could be apparently prolonged and as a result, a 24-h controlled-release dosage form of captopril could be achieved.

Furosemide (FR) is a weakly acidic drug and has a greater absorption window on the upper GIT. The bioavailability was enhanced by Ozdemir et al.  by preparing an inclusion complex of FR with beta-cyclodextrin (beta-CD) in a 1:1 proportion using the kneading method. After adding the excipients, floating tablets were prepared, which showed retention time of 6 h and AUC of about 1.8 times of the conventional dosage form. Similarly, Menon ^] observed around 15% increase in the bioavailability of FR by preparing monolithic modified release dosage form. Klausner et al. reported the absorption phase of levodopa (narrow absorption window) was significantly prolonged following gastroretentive dosage forms (GRDF) administration in comparison with Sinemet CR, which was solely depended on size and rigidity of the novel GRDF.

For the treatment of Helicobacter pylori-associated peptic ulcers a floating device was formulated by Yang et al.  with triple drug regimen (tetracycline, metronidazole and bismuth salt). HPMC and poly (ethylene oxide) were the major rate controlling polymeric excipients. Tetracycline and metronidazole were incorporated into the core layer of the triple layer matrix for controlled delivery, while bismuth salt could be included in one of the outer layers for instant release. Results demonstrated that sustained delivery of tetracycline and metronidazole over 6-8 h could be easily achieved while the tablet remained in floating state.

Eight healthy volunteers were observed in a pharmacokinetic and hemodynamic study by Hou et al. of diltiazem floating tablet. Floating tablets showed that the t½ (6.4 ± 4.4 h) and C _max (56 ± 23 ng/ml) were longer and lower than normal tablets as (2.3 ± 1.1 h and 96 ± 30 ng/ml, P < 0.01), respectively.

Streubel et al. prepared floating microparticles consisting of (i) Polypropylene foam powder; (ii) verapamil HCl as model drug; and (iii) Eudragit RS, ethylcellulose (EC) or polymethyl methacrylate (PMMA) as polymers and were prepared with oil in water solvent evaporation method. The microparticles exhibited good in vitro floating behavior. The drug release rate increased with increasing drug loading and with decreasing polymer amounts

Floating dosage forms: An overview

Floating dosage forms: An overview

Drug delivery systems are used for maximizing therapeutic index of the drug and reduction in side effects due to site-specific drug delivery. With the recent developments and advances in pharmaceuticals, frequently taken medicaments are incorporated in a single unit dosage form. This reduces the frequency of administration of medicament to the patient. The real challenge in the development of a controlled drug delivery system is not just to sustain the drug release but also to prolong the presence of the dosage form in the stomach or the upper small intestine until all the drug is completely released in the desired period of time. The residence of a drug delivery system in the upper part of the gastrointestinal tract (GIT) can be accomplished by several drug delivery systems, such as intragastric floating systems,  swelling and expandable systems,  bioadhesive systems, modified shape systems,  high-density systems, ^[ delayed gastric-emptying systems ^[and low-density super porous systems. This review deals with floating dosage forms, an oral novel drug delivery system. 

In general, the drug release is governed by various polymers, which are used in the formulation. These polymers entrap the drug material in the matrix form or form a membranous sheath around the drug. The polymer in either case controls the release rate of drug by diffusion or by erosion method. Such drug delivery systems are termed as controlled drug delivery systems, which release the drug(s) with a predictable kinetics. Other approaches and materials that have been reported are highly swellable hydrocolloids and light mineral oils, a mixture of sodium alginate and sodium bicarbonate, multiple unit floating pills that generate carbon dioxide when ingested, floating minicapsules with a core of sodium bicarbonate, lactose and polyvinyl pyrrolidone coated with hydroxypropyl methylcellulose (HPMC) and floating systems based on ion-exchange resin technology. Excipients used most commonly in these systems include HPMC, polyacrylate polymers, polyvinyl acetate, polyethylene glycol (PEG)-6000, Carbopol, agar, sodium alginate, calcium chloride, polyethylene oxide and polycarbonates. Drugs used in the formulation of floating dosage forms.

The oral dosage forms taken orally are very much affected by the gastric physiology. As it is the gastric residence time (GRT), which decides the retention time of oral dosage form in GIT, the gastric emptying (GE) of liquids in the fasted state is a function of the volume administered. The normal GE t½ is 46.5 ± 5.5 min. This sets an approximately 10 h limit for the delivery of drugs absorbed solely from the small intestine region. The various factors affecting GE include age, diseased state and diet. Normal aging is associated with various changes in gastrointestinal motility. The important factor is the impact of various age-related diseases on gastrointestinal motility in elderly patients; for example, long-standing diabetes mellitus may reduce GE in about 50%, depression significantly prolongs whole gut transit time, hypothyroidism may prolong orocecal transit time and chronic renal failure is associated with impaired GE. (Gastro intestinal transit time) In addition, various frequently used drugs in an elderly patients cause disordered gastrointestinal motility. These drugs include anticholinergics, especially antidepressants with an anticholinergic effect, opioid analgesics and calcium antagonists. Delayed GE or gastrointestinal symptoms occur in 30%-50% of patients with diabetes  as well as in chronic liver diseases. High electrolyte content tends to decrease GE.Glucose supplementation accelerates GE of glucose, viscous polysaccharides show delayed GE and slow transit through the small bowel. The GE is significantly slow during dehydration and at times the GE is very rapid as with liquid diet, emotional stress and exercise. Thus, oral controlled release drug delivery systems have limited use in the gastrointestinal controlled administration of drugs if the system cannot remain in the vicinity of the absorption site for lifetime of the drug delivery. The transit time for the mouth to the anus varies with each individual. Oral delivery for 24 h is possible for many drugs; however, the substance must be adequately absorbed throughout the whole GIT. A significant obstacle may arise if there is a narrow window for drug absorption in the GIT or if a stability problem exists in GI fluids or the drug is poorly soluble in the intestine or acts locally in the stomach. 

Taking these factors into consideration, investigators formulated a novel drug delivery system for controlled drug delivery at the stomach level, termed as floating tablets or Hydrodynamically Balanced Systems (HBS) or gastroretentive drug delivery systems to prolong the residence of the dosage forms in the stomach or somewhere in the upper small intestine until all the drug is released for the desired period. Gastroretentive systems can remain in the gastric region for several hours, and hence significantly prolong the gastric residence time of drugs. Prolonged gastric retention improves bioavailability, reduces drug waste, and improves solubility for drugs that are less soluble in a high pH environment. It has applications also for local drug delivery to the stomach and proximal small intestine. Gastroretention helps provide better availability of new products with new therapeutic possibilities and substantial benefits for patients.

Preformulation: In Development of dosage form

Preformulation: In Development of dosage form

The Concept of Preformulation:-

Almost all drugs are marketed as tablets, capsules or both. Prior to the development of these  major dosage forms, it is essential that pertain fundamental physical and chemical properties of the drug molecule and other divided properties of the drug powder are determined. This information decides many of the subsequent events and approaches in formation development. This first learning phase is known as preformulation.

Definition:-

Preformulation involves the application of biopharmaceutical principles to the physicochemical parameters of drug substance are characterized with the goal of designing optimum drug delivery system.

Before beginning the formal preformulation programs the preformulation scientist must consider the following factors :-

- The amount of drug available.

- The physicochemical properties of the drug already known.

- Therapeutic category and anticipated dose of compound.

- The nature of information, a formulation should have or would like to have.

Preformulation drug characterization in a structured program:-

Test	Method/ function Characterization
Fundamental
1) UV spectroscopy	Simple assay
2) Solubility	Phase solubility/ purity
a) Aqueous	Intrinsic & pH effect
b) pKa	solubility control , salt formation
c) Salt	Solubility, hygroscopicity & stability
d)Solvents	Vehicles & Extraction
e) ko/ w	Lipophillicity, structure activity
f) Dissolution	Biopharmacy
3) Melting point	DSC-polymorphism hydrate & solvent
4) Assay development	UV, HPLC, TLC
5) Stability
In Solution	Thermal, hydrolysis, pH
In solid state	Oxidation, proteolysis metal ion
Derived
6) Microscopy	Particle size and morphology
7) Bulk density	Tablet and capsule formation
8) Flow properties	Tablet and capsule formation
9) Compression properties	Acid / excipient choice
10) Excipient compatibility	Preliminary screen by DSC, Conformation by TLC

UV Spectroscopy :-

The first requirement of any preformulation study is the development of a simple analytical method for quantitative estimation in subsequent steps. Most of drugs have aromatic rings and/or double bonds as part of their structure and absorb light in UV range, UV spectroscopy being a fairly accurate and simple method is a performed estimation technique at early preformulation stages. The absorption Co-efficient of the drug can be determined by the formula:-

E =    AF / X 

Where ,            A = Asborbance

                        F= dilution factor

                         X = weight of drug (mg)

            It is now possible to determine connectration of drug in any solution by measuring absorbance.

            C =      AF / E mg/ ml

            Characterization of drug molecules is very important step at the preformulation phase of product development. Following studies are conducted as basic preformulation studies, special studies are conducted depending on the type of dosage form and the type of drug molecules.

1)         Solubility determination

2)         pKa determination

3)         Partition co-efficient

4)         Crystal properties and polymorphism

5)         Practical size, shape and surface area.

6)         Chemical stability profile.

Solubility Determination:-

The solubility of drug is an important physicochemical property because it effects the bioavailabilty of the drug, the rate of drug resale into dissolution medium and consequently, the therapeutic efficiency of the pharmaceutical product.

The solubility of the molecules in various solvents is determined as a first step. This information is valuable is developing a formulation. Solubility is usually determined in variety of commonly used solvents and some oils if the molecules is lipophillic.  

The solubility of material is usually determined by the equilibrium solubility method, which employs a saturated solution of the material, obtained by stirring an excess of material in the solvent for a prolonged until equilibrium achieved :-

Common solvents used for solubility determination are :-

·Water

·Polyethylene Glycols

·Propylene Glycol

·Glycerin

·Sorbitol

·Ethyl Alcohol

·Methanol

·Benzyl Alcohol

·Isopropyl Alcohol

·Tweens

·Polysorbates

·Castor Oil

·Peanut Oil

·Sesame Oil

·Buffer at various pHs

Aqueous Solubility :-

The availability of a drag is always limited and the preformulation scientist may only have 50 mg. Solubility dictates the ease with which formulation  for oral gavages and intravenous injection studies in animals are obtained the pKa allives the informed of pH to maintain solubility and to choose salts required to achieve good bioavailability from the solid state and improve stability and powder properties.

Intensic  Solubility (Co) :-

An increase in solubility in acid compared to aqueous solubility suggests a weak base and an increase in alkali, a weak acid . An increase in acidic and alkaline solubility suggest either impotence or zuitter ion behaviour. In this case there will be two pKa’s, one acidic & one basic . When the pavrity of the drug sample can be assured the solubility obtained in acid for a weak acid or albali for a weak base can be assured to be the instensic solubility (Co.) i.e. the fundamental solubility when completely unionized. The solubility should ideally be measured at two temperature.

1)4C to ensure physical stability and entered short term storage and chemical stability unit more definitive data are available. The minimum density of water occurs at 4C. This leads  to a minimum aqueous solubility.

2)37C to support biopharmaceutral evaluation .    

pKa Determination:-

Determination of the dissociation content for a drug capable of ionization within a ph rang of  1 to 10 is important since solubility and  consequently absorption, cab be altered by orders of magnitude with  changing pH. The Henderson – Hasseslebach  equation provides an estimate of the ionized and un ionized durg concentration at a particular pH.

For acidic compounds

pH = pKa + log  (un-ionized drug]) / [ionized drug])

Partition Coefficient :-

Partition Coefficient (oil/ water) is a measure of a drug’s lipophilicity and an indication of its ability to cross cell membranes. It is defined as the ratio of unionized drug distributed between the organic and aqueous phases at equilibrium.

P o/w = (C oil / C water) equilibrium.

For series of compounds, the partition coefficient can provide an empiric handle in screening for some biologic properties. For drug delivery, the lipophilic/ hydrophilic balance has been shown to be a contributing factor for the rate and extent of drug absorption. Although partition coefficient data alone does not provide understanding of in vivo absorption, it does provide a means of characterizing the lipophilic/ hydrophilic nature of the drug.

Since biological membranes are lipoidal in nature. The rate of drug transfer for passively absorbed drugs is directly related to the lipophilicity of the molecule. The partition coefficient is commonly determined using an oil phase of octanol or chloroform and water.

Drugs having values if P much greater than 1 are classified as lipophilic, whereas those with partition coefficient much less than 1 are indicative of a hydrophilic drug.

Although it appears that the partition coefficient may be the best predictor of absorption rate, the effect id dissolution rate, pKa and solubility on absorption must not be neglected.

Dissolution :-

The dissolution rate of the a drug is only important where it is the rate limiting step in the absorption process. Kaplan suggested that provided the solubility of a drug exceded to mg/ ml at pH , 7 no bioavailability or distinction related problems were to be expected. Below / mg/ ml such problems were quite possible and salt formation could improve absorption and solubility by controlling the pH of the microenvironment, independently of the drug and dosage forms position within the GI ireat.

Intrinsic Dissolution Rate :-

When dissolution is controlled solely by diffusion the rate of diffusion is directly proportional to the saturated concentration of the drug in solution under these conditions the rate constant K₁ is defined by

K₁ = 0.62 D^2/3 v ^1/6 w^1/2

Where, V is the kinemative viscosity

W is the anguter velocity of a rotating disc of drug.

Common Ion Effect :-

A common ion significantly reduces, the solubility of a slightly soluble electrolyte. The ‘selling out’  results from the removal of water molecules as solvent  owing to the completing hydration of other ions. The reverse process ‘salting in’ qries with large anions e.g. benzoate, salivate which open the water structure. These hydro topics increase the solubility of properly water soluble compounds such as diazepam.

Melting Point :- 

The melting point of  a drug can be measured using three techniques :-

1)Capillary Melting

2)Hot Stage Microcopy

3)Differential scanning calorinetry or thermal Anaylysis.

Capillary Melting :-

Capillary melting gives information about the melting range but it is different to assign an accurate melting point.

Hot Stage Microcopy :-

This the issued observation of melting under a microscope equipped with a heated and lagged sample stage. The heating rate is controllable and upto three transitions can e registered.  

Differential Scanning  Calorimeltry and thermal analysis :-

Differential thermal analysis (DTA) measures the temperature difference between the sample and a reference as a function of temperature or time when heating at a constant rate differential scanning calorinetry (DSC) is similar to DTA except that the instrument measures the amount of energy required to keep the sample at the same temperature as the reference i.e. it measures the enthalpy of transition.

Crystal Properties and Polymorphism :-

Many drug substance can exit in more than one crystalline from with different space lattice arrangements. This property is known as polymorphism. Polymorphs generally have diffrent melting points, x-ray diffraction patterns and  solubility even though they are  chemically identical.

Differences in the dissolution rates and solubilities of different polymorphic forms of a given drug are very commonly observed. When the absorption of a drug is dissolution rate limited, a more soluble and faster-dissolving from may be utilized to improve the rate and extent of bioavailability.

For drugs pane to degradation in the solid state, physical form of the drug influences degradation. Selection of a polymorph that is chemically more stable is a solution in many cases. Different polymorph also lead to different morphology, tensile strength and density of power bed which all contribute of compression characteristics of materials. Some investigation of polymorphism and crystal habit of a drug substance as it relates to pharmaceutical processing is desirable during its Preformulation evaluation especially when the active ingredient is expected to constitute the bulk of the tablet mass. Although a drug substance may exist in two or more polymorphic forms, only one form is theromdynamically stable at a given temperature and pressure. The other forms would convert to the stable form with time. In general, the stable polymorph exhibits the highest melting point , the lowest solubility, and the maximum chemical stability. Various techniques are available for the investigation of the solid  state. These include microscopy (including hot stage microcopy), infrared spectrophotometry, single-crystal x-ray and x-ray power diffraction, thermal analysis, and dilalometry.

Particle Size, Shape and Surface Area:-

Bulk flow, formulation homogeneity, and surface-area controlled processes such as dissolution and Surface morphology of the drug particles. In general, each new drug candidate should be tested during Preformulation with the smallest particle size as is practical to facilitate preparation of homogeneous samples and maximize the drug’ s surface area for interactions.

Various chemical and physical properties of drug substances are affected by their particle size distribution and shapes. The effect is not only on the physical properties of solid drugs but also, in some instances, on their biopharmaceutical behavior. It is generally recognized that poorly soluble drugs showing a dissolution- rate limiting step in the absorption process will be more readily bio available when administered in a finely subdivided state rather than as a coarse material.

In case of tablets, size and shape influence the flow and the mixing efficiency of powders and granules. Size can also be a factor in stability: fine materials are relatively more open to attack from atmospheric oxygen, the humidity, and interacting axcipients than are coarse materials.

- Determination of particle size

-Determination of surface area

Particle size Determination:-

Though microscopy is the simplest technique of estimating size ranges and shapes, it is to slow for quantitative determination the material is best observed as a suspension in non dissolving fluid. Saving is less useful technique at preformulation storage due to lack of bulk material. Andreason  pipette is based on the rate difference of sedimentation of different particles, but techniques like this are seldom used due to their tedious nature instruments based on light scattering, (Royco), light blockage (HIAC) and blockage of electrical conductivity path (coulter counter) are available.

Surface Area Determination:-

Surface area is most commonly determined based on brunaver emette teller (BET) theory of adsorption. Most substances adsorb a mono molecular layer of gas under certain conditions of partial pressure of gas and temperature. Knowing the monolayer capacity of adsorbent and the area of absorbale molecule, the surface area can be calculated the adsorption process is carried out with nitrogen at-195 degree Celsius at a partial pressure attainable when nitrogen is in a 30% temperature with an inert gas (helium). The adsorption takes place by virtue of vander wall’s forces.

Power Flow Properties:-

When limited amounts of drugs are available Power flow properties can be evaluated by measurements of bulk density and angle of repose. Changes in particles size, and shape are generally very important an increase in crystal size or a more uniform shape will lead to a small angle or rpose  and a smaller Carr’s index. 

Bulk Density :-

 Knowledge of absolute and bulk density of the drug substance is Very useful in Having some idea  as to the size of final dosage form the density of solids also of affects their flow Properties Carr’s compressibility index can be used to predict the flow properties based on density measurement.

Carr’s index (%)          =          Tapped density – Pored density *100

                                                                        Tapped density

A similar index has been defined by Hausner :

Hausner ratio   =          Tapped density

                                      Pored density

Angle of repose:-

The maximum angle which is formed b/w the surface of a pile of powder and horizontal surface is called the angle of repose.

Relationship between flow, angle of repose, Carr’s index fee power flow

Flow	Angle of repose	Carr’s index ( % )
Excellent	<25	5-15
Good	25-30	12-16
Fair to passable	30-40	18-21
Poor	> 40	23-35
Very Poor		33-38
Extremely Poor		>40

Chemical stability profile:

Preformulation stability studies are usually the first quantitative  assessment of chemical stability of a new drug. These studies include both solution and solid state experiments under condition typical for the handing, formulation, storage, and administration of a drug candidate as well as stability in presence of other recipients.

Factor effecting chemical stability critical in rational dosage form design include temperature, pH and dosage form diluents. The method of sterilization of potential product will be largely dependent on the temperature stability of the drug. Drugs having decreased stability at elevated temperatures cannot be sterilized by autoclaving but must be sterilized by another means, e.g., filtration. The effect of pH on drug stability is important in the development of both oral administration must be protected from the highly acidic environment of the stomach. Buffer selection for potential dosage forms will be largely based on the stability characteristic of the drug.

- Solid state stability

- Solution phase stability

- Compatibility studies : stability in the Presence of excipients

- Typical stability protocol for anew Chemical Entity

Solid state stability:-

Chemical instability normally results from either of the following reaction :- hydrolysis, oxidation, photolysis and pyrolysis, Chemical structure of the drug is the determination of drug to either of these attacks. Esters and lactase and to lesser extent, amides are to prone to solvolysis . Instauration or electron rich centre in the structure make the molecule vulnerable for free radical mediated or photo-catalysed oxidation. physical properties of drugs. Amorphous materials are less stable than their crystalline forms. Denser materials are more stable to ambient stress.

Elevated temperature studies:-

The elevated temperatures commonly used are 40, 50, and 60 degree centigrade with ambient humidity. The samples stored at highest temperature are observed weekly for physical and  chemical changes and compared to an appropriate control . If a substantial change is seen, samples stored at lower temperature are examined . If no changesisseen after 30 days at 60 degree centigrade, the stability prognosis is excellent .

Stability under high humidity conditions :-

Solid drug samples can be exposed to different relative humidity conditions by keeping them in laboratory desiccators containing saturated solutions of various salts. The closed desiccators in turn are kept in oven to provide constant temperature. The preformulation data of this nature are useful in determining if the material should be protected and stored in controlled low humidity environment or if non aqueous solvent be used during formulation.

Photolytic stability :-

Many drugs fade or dorpen on exposure light. Though the extent of degradations small and limited to the exposed surface area, it presentsanaesthetic problem. Exposure of drug 400 and 900 foot-candles of illumination for 4 and 2 week periods respectively is adequate to provide some idea of photosensitivity. Resulting data may be useful in determining if an amber colored container is required or if color masking bye should be used in the formulation .

Stability to Oxidation :-

Drug’s sensitivity to oxidation can be examined by exposing it to atmosphere of high oxygen tension. Usually a 40% oxygen atmosphere allows for rapid evaluation. A shallow layer of drug exposed to a sufficient headspace volume ensures that the system is not oxygen limited. Samples are kept in desiccators equipped with three-way stop cocks, which are alternatively evacuated and flooded with desired atmosphere. The process is repeated 3 or 4 times to ensure 100% desired atmosphere. Results may be useful in predicting if an antioxidant is required in the formulation or if the final product should be packaged under inert atmospheric conditions.

Compatibility studies :-

The knowledge of drug excipients interaction is useful for the formulation to select appropriate excipients. The described preformulation screening of drug excipients interaction requires only 5mg of drug in a 50% mixture with the excipients to maximize the likelihood of obscuring an interaction . Mixtures should be examined under nitrogen to ultimate oxidation and paralytic effect at a standard heating rate on DSC, over a temperature range, which will encompass any thermal changes due to both the drug and appearance or disappearance one or more peaks in themogrames of drug excipient mixtures are considered of indication of interaction.

Solution phase stability:

As compared with the dry form, the degradation is much rapid in solution form. It is important ascertain that the drug doesn’t degrade when exposed to GI fluid. The pH based stability study, using different stimulator GI condition can be designed. A poor solution stability of drug may urge the formulator to choose a less soluble salt form, provided the bioavailability is not compromised

Absorption behavior:

It is essential to test the in vivo behavior of the new drug for successful formulation of a dosage from good bioavailability. Partial in vivo and in vitro test are designed to study pharmacokinetic profile of the drug.

               

Reference:

1.       G. Banker and C.T. Rhodes, Modern Pharmaceutics, Marcel Dekker, Inc., 2000.

2.       H. Brittain, Physical Characterization of Pharmaceutical Solids, Marcel Dekker, Inc., 1995.

3.        H. Brittain, Polymorphism in Pharmaceutical Solids, Marcel Dekker, Inc., 1999.

4.       S.R. Byrn, R.R. Pfeiffer and J.G. Stowell, Solid State Chemistry of Drugs, Second Edition, SSCI, Inc.,1999.

5.       K.A. Connors, G.L. Amidon, and V.J. Stella. Chemical Stability of Pharmaceuticals (Second Edition), John Wiley & Sons, Inc., 1986.

6.       E.F. Fiese and T.A. Hagen, “Preformulation”, Chapter 8 in the Theory and Practice of Industrial Pharmacy, Lea & Febiger, Philadelphia, 1986.

7.       M. Gibson, Pharmaceutical Preformulation and Formulation, HIS Health Group, Englewood, CO, 2001.