Linearity Of Polymer Chain

Published Date: 02 Nov 2017

As per the previous discussion a lot many issues have been raised including the difficulties in purification, scale-up or commercial manufacturing which have limited the use of natural biodegradable polymers. While concurrently the synthetic biodegradable polymers have proved its potential with wide range, applicability, availability and cost effectiveness. Over the past few decades, synthetic polymers have been actively studied for use in drug delivery systems. Several classes of synthetic polymers have been proposed, which include poly-(ester)s, poly-(anhydride)s, poly-(carbonate)s, poly-(amino-acid)s, poly-(amide)s, poly-(urethane)s, poly-(ortho-ester)s, poly-(imino-carbonate)s, and poly-(phosphazene)s [95-100].

2.6.2.1 Poly (ester)s

The most extensively investigated class of polymers pertaining to toxicological and clinical data comprise aliphatic poly (ester)s consisting of lactic and glycolic acid. Their corresponding polymers, poly (lactic acid), poly (glycolic acid), and copolymer poly (lactic-co-glycolic acid) have found widespread commercial application as drug delivery devices. Since, the high molecular weight polymers of glycolic and lactic acid cannot be obtained by condensation of the related α-hydroxycarboxylic acids, these polymers are typically produced by ring-opening polymerization of their cyclic dimers in the presence of catalysts such as stannous octoate. (Fig. ). Lactic acid comprises of an asymmetric α-carbon which is typically described as D or L form and thus three different plausible polymers include poly (L-lactic acid), poly (D-lactic acid), and poly (DL-lactic acid). Thus far, poly (L-lactide) and poly (DL-lactide) have received the most attention among these poly (lactide)s (PLAs).

Fig….: Ring-opening Polymerization of PLA (R=H) or poly (glycolide) (R=CH3).

The diverse properties of the polymers including mechanical, thermal, and biological are markedly influenced by their stereochemistry. Poly (lactide-co-glycolide) (PLGA) embodies the ‘‘gold standard’’ of biodegradable polymers. The properties of these copolymers can be tailored by varying the ratio of PLA and poly (glycolide). The mechanism of degradation in poly (ester)s is classified as bulk degradation with random hydrolytic cleavage of the ester bond linkages in the polymer backbone. The accumulation of acidic degradation products in the polymeric matrix as a result of reduced diffusion especially in larger devices eventually leads to an autocatalytic effect on degradation of device. Chemical structures of various homopolymers and copolymers are as follows:

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Poly (L-lactide) Poly (d, l-lactide)

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Polyglycolide Poly (lactide-co-glycolide)

Fig….: Various Biodegradable Polyesters.

2.6.2.1.1 PGA, PLA and PLGA

Currently most frequently used biodegradable polymers for drug delivery include poly (glycolic acid) (PGA), poly (lactic acid) (PLA) and poly (lactide-co-glycolide) (PLGA), which is typically attributable to their long history of use as medical sutures. PGA is the simplest linear aliphatic polyester which is usually synthesized from the dimer of glycolic acid i.e. glycolide. The first totally synthetic absorbable suture was developed by PGA. It is highly crystalline (45-55%) with a high melting point (220-225oC) and a glass transition temperature of 35-40 oC. Owing to its high degree of crystallization, PGA is insoluble in most organic solvents. Fibers made from PGA exhibit high strength and modulus and these being extremely stiff, thus can’t be used as sutures. Glycolide has been copolymerized with lactide, the dimmer of lactic acid, to reduce the stiffness of the resulting fibers [88-93].

PLA is normally synthesized from lactide monomers. Lactide exists as two optical isomers, d and l. L-lactide is the naturally occurring isomer, and dl-lactide is the synthetic blend of d-lactide and l-lactide. Poly (l-lactide) is about 37% crystalline with a melting point of 175-178 oC and a glass transition temperature of 60-65 oC. The degradation of poly (l-lactide) is very slow, requiring more than 2 years to be completely absorbed. It exhibits high tensile strength and low elongation and consequently has a high modulus that makes it more suitable for load-bearing applications such as sutures.

Poly (dl-lactide) is an amorphous polymer exhibiting a random distribution of both isomeric forms of lactic acid, and accordingly is unable to arrange into an organized crystalline structure. The versatile properties of this material such as lower tensile strength, higher elongation, and a much more rapid degradation time, make it more suitable as a drug delivery system. Using the properties of PGA and PLA as a starting point, it is possible to copolymerize the two monomers to extend the range of the homopolymer properties. PLGA has been developed for both sutures and drug delivery applications. It is imperative that the copolymer composition and the mechanical and degradation properties of the materials does not bear a linear relationship between them. For instance, a copolymer of 50% glycolide and 50% dl-lactide degrades faster than either homopolymer [94-99].

Fig….: Chemical structure and Synthesis of Poly (lactic acid), Poly (glycolic acid), and Poly (lactic-co-glycolic acid).

2.6.2.1.2 PLA and PEG Copolymers

Although the PLA and PLGA are now commonly used, but still research is going on for designing and synthesizing new polymers for the application of drug delivery. One very promising strategy is to copolymerize PLA and poly (ethylene glycol) (PEG). PEG has been known as an excellent biomaterial due to its biocompatibility, hydrophilicity and flexibility. It is also referred as poly (ethylene oxide) (PEO) at high molecular weight. Copolymerization of hydrophobic PLA and hydrophilic PEG can provide a balance between the two opposite parts. Furthermore, different supramolecular structures can be achieved by different monomer combinations and preparation processes to meet various medical requirements. The PEG chains minimize non-specific fouling of the device surface with bio-components such as proteins. The uptake of nanoparticles by the reticuloendothelial system (RES) can be reduced. Di-block PLA-PEG copolymer can also form micelles in aqueous environment with PEG on the surface [100, 102, 105].

In contrast to surfactant micelles, these polymeric micelles are more stable, have a lowered critical miceller concentration, and have a slower rate of dissociation, thus permitting the retention of loaded drugs for a longer period of time and, eventually, achieving higher accumulation of a drug at the target site. Furthermore, they have a size range of several tens of nanometers with a considerably narrow distribution, which is crucial in determining their body disposition. A family of star-block copolymers from multi-arm PEO and l-lactide or l-lactide/glycolide has been recently reported. In vitro degradation test results on these polymers show that the biodegradation consists of an initial slow-rate period in the first 2-3 weeks, which makes them an excellent drug carrier, and an exhaustive degradation period, which provides the way for renal excretion.

Thermo-sensitive hydrogels have been prepared from either PLA-PEO di-block or PEO-PLA-PEO tri-block polymers. The hydrogel can be loaded with bioactive molecules in an aqueous phase at an elevated temperature (around 45 oC), where a sol is formed. The polymer is injectable as well when used in this form. Upon subcutaneous injection and ensuing rapid cooling to body temperature at 37 oC, the polymer form a gel that can act as a sustained-release matrix for drugs. The gel-sol transition temperature can be well controlled by the molecular weight of PLA segment. Both high molecular weight proteins and low molecular weight hydrophobic drugs can be loaded and released [97-101].

The release rate is controllable by the initial drug loading and the polymer concentration. In one investigations Biotin has been conjugated to the PLA-PEG copolymer to form a new polymer PLA-PEG-biotin. In this new polymer, the PLA component provides structural integrity to the fabricated devices. The PEG block acts as a hydrophilic coating to avoid the uptake of RES. The third part of the polymer, i.e. biotin moiety, allows facile surface engineering using aqueous solution of avidin. Avidin posses a tetrameric structure with four binding sites for biotin. One of these sites of avidin is utilized for the binding of biotin, while biotinylated ligand motifs get bound to other available free binding sites, which in turn be used for targeting to tumor cells.

2.6.2.2 Poly (ortho esters)

The obligation to develop biodegradable polymers in wherein drug release exhibits surface erosion mechanism was the existent impetus behind the designing of poly (ortho esters) for drug delivery. Most studies have entailed the addition of polyols to diketene acetals to synthesis poly (ortho esters). In current scenario researchers have described the synthesis and application of the 3,9-diethylidene-2,4,8,10-tetraoxaspiro[5,5] undecane (DETOSU)-based poly (ortho esters). The basic structure is formed by the addition of the DETOSU monomer to a di-ol to form the chemical structure shown in Figure…...

The DETOSU-based poly (ortho esters) comprises of acid labile ortho ester linkages in their backbone. In aqueous environments, the pentaerythritol dipropionate and di-ol monomers are formed as result of hydrolysis of ortho ester groups. The pentaerythritol dipropionate gets hydrolyzed further to pentaerythritol and acetic acid. The acid-catalyzed hydrolysis of POE can be modulated by introducing either an acidic or a basic excipient into the matrix system. Invariably, the addition of acidic excipients enhances the rate of hydrolysis. Alternatively, the basic excipients facilitate surface erosion by diffusing out of the surface region and thereby stabilizing the bulk of the matrix [103-105].

Fig….: Degradation of the 3, 9-bis (ethylidene-2, 4, 8, 10-tetraoxaspiro [5,5] undecane) (DETOSU)-based poly (ortho esters).

This approach has been employed in the treatment of periodontal disease by utilizing the temporal controlled release of tetracycline for over a period of weeks. Of late, numerous alterations in di-ol structure have been attempted to evade the necessity for acidic excipients. These new poly (ortho ester) structures address the problem of unpredictable degradation kinetics arising as consequence of diffusion of acidic excipient from matrices. Recent research investigations have described the synthesis of self-catalyzed poly (ortho esters) that contains glycolide segments. Once glycolide segments degrade, its degradation products catalyze ortho ester bond breakage, hence forming a self-catalyzing system.

The synthesis of these polymers is shown in Figure…... A commendable aspect of the DETOSU systems is the ability to control the mechanical properties by virtue of altering the di-ol monomer ratios within the final polymeric structure. Scientists have shown that an increase in the proportion of rigid di-ol in the polymers containing a rigid di-ol monomer (trans-cyclohexanedimethanol) (CDM) and a flexible monomer (1, 6-hexanediol) can lead to gross variation (between 20 and 105°C) in glass transition temperature of polymers. This control can also be achieved with the glycolide-containing polymers [98-104].

Fig….: Synthesis of a Self-catalyzed poly (ortho ester) containing Glycolic acid dimer.

2.6.2.3 Poly (ethylene glycol) block Copolymers

Poly (ethylene glycol) entails excellent and outstanding biocompatibility which can be ascribed to it’s hydrophilic nature. This attribute leads to formation of hydrogen bonds between water and the polymer chains, and also inhibits protein adsorption. Consequently, the presence of poly (ethylene glycol) chains at the surface of a parenteral device prolongs the biological events such as endocytosis or phagocytosis which in turn increases blood circulation times. One of the emerging uses for inclusion of PEG in a controlled release system arises from its interaction with protein. It has been established that the conjugation of proteins with PEG provide prolonged protein circulation life, reduced immunogenicity and antigenicity as well.

PEG chains at the surface provide the incorporated substance longer circulation time in the body by prolonging biological events such as endocytosis, phagocytosis, liver uptake and clearance, and other adsorptive processes. PEG can be tailored with a range of terminal functionalities, which lead to its easy incorporation into copolymer systems. Further, the synthetic modification of PEG is facilitated by the presence of chain-end hydroxyl groups. Besides, the block copolymers of poly (ethylene glycol) and PLA or PLGA have been synthesized for the encapsulation of various APIs. Di-block PLA-PEG and tri-block PLA-PEG-PLA systems have been synthesized and characterized with various PLA contents. Recent research has evolved a thermo-sensitive PLA-PEO hydrogels that exhibit temperature dependent gel-sol transition for use as injectable drug delivery systems [87-93].

2.6.2.4 Poly (anhydride)s

Although, Poly (anhydride)s contains water-sensitive bonds, yet it’s relatively more hydrophobic than the poly (ester)s which eventually leads to reduced water permeation into the polymer bulk. Consequently, poly (anhydride)s predominately undergo surface erosion by cleavage of the anhydride bonds at the surface of the device. The most widely studied poly (anhydride)s are based on sebacic acid, p-(carboxyphenoxy) propane, and p-(carboxyphenoxy) hexane (Fig. ). In recent trends and implication of the polymeric delivery; interstitial administration of an antitumor agent using a loaded polymeric disc composed of poly (carboxyphenoxypropane-sebacic acid) has been successfully performed.

Fig…: Structures of poly (anhydride)s based on Monomers of Sebacic acid (A), p-(carboxyphenoxy) propane (B for x=3) and p-(carboxyphenoxy) hexane (B for x=6).

2.6.3 Properties of Biopolymers

In current research trends the biodegradable polymers have its own place and added advantage due to its very specific phenomenal properties. The lactide and glycolide homo and copolymers have potentially exhibited wide versatality and applicability in controlled drug delivery. A broad spectrum of these polymers in accordance to performance characteristics can be obtained by precise and careful combination of certain variables; which are as follows-

Molecular weight of polymer

Linearity of polymer chain

Ratios of co-polymer

Stereochemistry of the monomer

2.6.3.1 Molecular weight of Polymer

Various classes of biopolymers including polyesters are commonly available in a wide range of molecular weights, commercially. The stated property affects biodegradation and resultant release profile and ultimately affects the performance characteristics of the delivery system. Higher molecular weight leads to increment in polymeric viscosity of the solutions and hence affects not only the microsphere size and sphericity but also the entrapment efficiency. Biological properties of these aliphatic polyesters have been studied by various teams of researchers who conclude about the biocompatibility and histocompatability of these polymers.

A group of researchers have disclosed that PLA was found to be suitable for surgical sutures and vascular grafts because it elicited no immunological response due to the absence of peptide chain and the biodegradable nature of the polymer. PLA and PLGA are degraded to lactic acid and glycolic acid which are ultimately excreted as CO2 and H2O from the body; exhibiting no toxicity. Histopathological studies have shown mild inflammatory reaction after the administration of lypressin-loaded polymeric microcapsules. However the exact cause of the reaction is not known; as it may be due to irritation, or actual chemical reaction of polymeric components with body [103-107].

2.6.3.2 Linearity of Polymer chain

Polymer chain linearity plays a key role in determination of hydrophilicity/hydrophobicity of the polymeric component. The outcome of the chain linearity affects the hydrophilicity of the polymer, which ultimately affects the degradation rate leading to tailor the release profile of the API; entrapped within the finished dosage form developed from the same polymer. The major associated phenomenon of chain linearity i.e. the extent of block or random structure present in the copolymer also affects the rate of hydration. Needless to state that rate of hydration will exhibit a governing role over degradation pattern of the finished polymer block; which will significantly alter the time frame of controlling the release rate of entangled candidate drug substance [102, 104, 106].

2.6.3.3 Ratios of Co-polymer

Factors affecting the biodegradation pattern as well as profile of various polymers depend over different co-polymer ratios, leading to different crystallinities, glass transition temperature (Tg) and hydrophilicities. The crystallinity of the co-polymers of lactide and glycolide depend on the molar ratio of two monomer components. PLGA containing < 70% glycolide content are amorphous. PLA, because of an additional methyl group is more hydrophobic than other glycolide polymer, which leads to lower water uptake and hence results in slower degradation patterns. Generally, the co-polymers having the 50:50 ratio degrades quicker than not only the homopolymers but also from other ratios; proving its least stable tendency over any other ratio or the homopolymer. Different polymer forms exhibits varying range of crystallinities, different hydrophilic behavior and solubility profiles [104]. These parameters ultimately affect the biodegradation and release profiles. Crystallinity and water uptake are considered as the key factors in determining the rates of in vivo degradation. Current research investigates that water uptake increases as glycolide ratio in copolymer increases.

2.6.3.4 Stereochemistry of the Monomer

Stating from the previous discussion; crystallinity of the co-polymers not only depends on the molar ratio of two monomer components but also relies on stereochemistry of the monomer. The racemic poly (DL-lactide) is less crystalline and thus has lower melting point than the stereo-regular forms of the same, i.e., D-PLA and L-PLA. Recent researches have revealed that crystalline domains and stereo-irregularity inhibit the degradation phenomenon of the polymer. Stereoregular or racemic lactides and co-polymers with < 50% glycolides are soluble in organic solvents as halogenated hydrocarbons, tetrahydrofuran (THF), dioxane etc. whereas glycolide rich polymers are soluble in exotic solvents like hexafluoro- isopropanol [103-107].

2.6.4 Degradation of Biopolymers

Biodegradable polymers may degrade through various means including enzymatic degradation, hydrolytic degradation, and microbial degradation. It is generally now admitted that in the case of aliphatic polyesters such as PLA, PGA and their copolymers, enzyme involvement is unlikely at the early stages of degradation in vivo or under outdoor conditions. However, enzymes contribute at the later stages, especially when soluble by-products are released. In contrast, for rubbery polymers like cross-linked PCL, enzymes seem to be active from the very beginning via surface erosion phenomena. Hydrolytic degradation of aliphatic polyesters involves four main phenomena, namely water absorption, ester cleavage, diffusion of soluble oligomers and solubilization of fragments. Some microorganisms use lactic acids, PLA oligomers and polymers, and PLGA copolymers as sole carbon and energy sources under controlled or natural conditions.

Aliphatic poly esters comprising of lactide/glycolide polymer chains undergo biodegradation through bulk erosion which are cleaved by hydrolysis to the monomeric acids and ultimately get eliminated from body through Krebs cycle, chiefly as carbon dioxide and in urine. Since the hydrolysis rate is dependent only on significant changes in temperature and pH or presence of catalysts so eventually petty divergence is discernible in the rate of degradation at different body sites. The role of enzyme in the biodegradation of the polymers has been still ambiguous. Hitherto reports nullified the involvement of enzymes during the bioerosion of lactide/ glycolide polymers occurring by means of hydrolysis, yet recent investigation has suggested that the enzymes do play a considerable role in the breakdown of these polymers in body. However much of these speculation are based on the difference observed between in vitro and in vivo disintegration rates rather than direct study. [101-106].

Table….: Biodegradation time of Lactide/glycolide Polymers.

Polymer

Degradation time (months)

Poly (l-lactide)

18 - 24

Poly (dl-lactide)

12- 16

Poly (glycolide)

2 - 4

Poly (dl-lactide-co-glycolide) (50:50)

2

Poly (dl-lactide-co-glycolide) (65:35)

3 - 4

Poly (dl-lactide-co-glycolide) (85:15)

5

Poly (dl-lactide-co-glycolide) (90:10)

2

Lactide glycolide polymers show wide range of hydrophilicity which makes them versatile in designing controlled release system. It has been demonstrated by various researchers that the efficiency of water up take increase as the glycolide ratio in the co-polymer increases. Table….. clearly indicated the effect in degradation tenure varying with the copolymer ratio of lactic and glycolic acid. In current trends and implications, synthesis of lactide/glycolide polymers branched with different polyols polyvinyl alcohol and dextran acetate with significant change in the degradation profile of these polymers from that of linear polylactides were also reported.

2.6.5 Selection criteria for Biodegradable Polymers

Formerly, the researchers usually used hydrophobic polylactic acid (PLA) for drug microencapsulation with biodegradable polymers. However, for the last two decades, poly (lactic-co-glycolic) acid (PLGA) has been frequently employed as the biodegradable polymer for experimental and commercial drug encapsulation. This might be due to the typically slow degradation and drug release rate for PLA that can deliver drugs over months (e.g., Trenantone®), whereas PLGA degrades faster and can meet 2-4 week release criteria (e.g., Enantone®) that were often desired for initially developed long acting parenteral formulations of previously daily administered drugs [108-113].

The selection of a biopolymer for efficient pilot microencapsulation trials might be simplified by having knowledge of the followings; best route of administration for the specific drug; exact mass of polymeric microparticles required per unit dose; expected release rate in order to meet a therapeutic concentration; feasibility of administration of total required dose to maintain therapeutic drug blood level for desired frame of time. Nevertheless, the drug release should be quicker than the complete degradation of the respective polymer, yet the degradation times might help to choose a suitable polymer for the development of controlled release polymeric parenteral systems.

2.6.5.1 Polymer degradation Behavior

As per the preceding discussion, PLGA was found to be the most studied matrix of biodegradable microparticles. The polymer properties, e.g., the amount of water-uptake and the degradation time, can be adjusted by apposite selection of molecular weight, the polymer end-group, the lactide/glycolide ratio and in addition, the crystallinity of the polymer also play a key role as in case of poly-lactic acid (PLA). Other enforcing aspects that affect the polymer degradation include the size of the microparticles, the pH, and the temperature of the medium. Additionally, other reasons for the intensive use of PLA/PLGA are its approval for use in humans for numerous biomedical and pharmaceutical products in the US and Europe, its commercial accessibility (e.g., Resomer®, Lactel®), and its good solubility in numerous organic solvents [95, 98, 99].

. Commonly, a 50:50 PLGA with a low to medium molecular weight (e.g., Resomer® RG 502 or 504) provides as long as 4-6 week release, and one might consider a polymer with a higher lactide/glycolide ratio, if a slower release is entailed. Furthermore, the water-uptake and degradation rate of the particles will be influenced by the type of the polymer end-group. For instance, the free carboxyl groups lead to much more swelling of the matrix compared to the capped polymer bearing an aliphatic group at the extreme end of the polyester chain (e.g., Resomer® RG 503H vs. Resomer® RG 503), with methyl, ethyl, and lauryl alcohols being very common end-groups for capped polymers. The faster degradation of free-acid end-group PLGA can be ascribed to the access of additional water and catalytic activity of instantly present free carboxyl groups [109, 110].

In vivo polymer degradation was shown to be quicker as compared to in vitro assays in buffer solution. This can be ascribed to a plasticizing effect of biological substances such as lipids, or possibly even the immunological response (which could trigger local release of harmful substances like radicals). Also, aggregation of microparticles in the tissue might increase the retention of acidic products in the aggregate and thus, accelerate autocatalytic chain scission. Determinations by various means including EPR spectroscopy, confocal imaging of pH-sensitive dyes and liquid chromatographic analysis or titration of acidic degradation products undoubtedly reveals that acidic products from the hydrolytic degradation of PLGA accumulate inside the microparticles. Two parameters viz the water-soluble content of acidic monomers/oligomers in the polymer matrix and the corresponding polymer-water partition coefficients of the same acids successfully predict the acidic microclimate pH in PLGA. The acidic microclimate has been shown to stabilize certain hydrophobic drugs with maximum stability below pH 4, although it has been considered to be disadvantageous for proteins and drugs that are sensitive to hydrolysis [104-107].

2.6.5.2 Polymer mixtures and Alternative PLGA co-polymers

In some instances it was observed that the release of hydrophobic drugs might be too slow from PLGA (50:50) copolymers. A faster release for the hydrophobic anticancer drug was discerned due to higher porosity eventually resulted from the use of a PLA-PEG-PLA block polymer instead of PLGA (50:50). PLGA-glucose star-shaped polymer, with glucose being the initiator molecule for polymerization, has successfully entered the market for octreotide delivery (Sandostatin LAR® Depot). The first methods employed to insure continuous release of peptides and hydrophobic drugs included the use of blends of high molecular weight (Mw) polymer with a small portion of a low Mw polymer, or use of low Mw polymer altogether. The incessant drug release by these methods invariably involved minimizing of lag phase to polymer mass loss and release. Such lag phases may appear in situations such as after the initial burst release of drug from surface-near domains in medium to high molecular weight PLA/PLGA, and also when diffusion controlled release through the dense matrix is limited and the generation of matrix microporosity by hydrolytic polymer degradation takes time depending on polymer type, Mw, and matrix geometry [99-103].

The advantageous effect of polymer blends is often rationalized by the fact that low Mw PLGA degrades faster to the critical Mw that ultimately allows their removal from the matrix, forms pores, and thus more transport paths are available for water to access the particle core and drug being released. The advantageous effect of polymer blends is often rationalized by the fact that the low Mw PLGA degrades faster to the critical Mw, allow their removal from the matrix, forms pores, and thus lead to availability of more transport paths for water to access the particle core and the ensures the release of drug. Also, during polymer degradation the increasing number of hydrophilic carboxyl group enhances the matrix hydrophilicity and water-uptake for medium and high Mw PLA/PLGA and, accordingly, the instant presence of more of such groups for blends with uncapped, low Mw PLGA will accelerate water-uptake.

2.6.5.3 Polymer properties Influencing Drug release

Drug release from a polymeric matrix is an important phenomenon in selecting the polymer for the development of polymeric microparticles; as it will significantly affect the criteria of selection of polymer, as per the need of the delivery system. Drug release could be potentially affected by various factors including drug nature, polymer properties and morphology of the matrix. Two important polymer properties that influence drug release are; a) Molecular weight and molecular weight distribution. It reflects the size and size distribution of a polymer. While we may expect qualitatively that drug diffusion rate decreases with increasing molecular weight, the critical factor that governs drug diffusion is determined by the overall microstructure of the polymer in the presence of diffusing and other foreign species. b) Glass transition temperature. It can be modified by changing the strength of the secondary forces within the polymer [102-107].

This can be accomplished by introducing an additive, such as a plasticizer, to the polymer. However it could also be modified through formation of copolymer. Drug transportation is modeled by migration of the penetrant through holes or free volume within the polymer. Therefore, the rate of transport is based on the probability of creating a hole of sufficient size to accommodate the penetrant, and the probability for this penetrant to have sufficient energy to enter this hole. At temperatures significantly higher than the Tg, both probabilities must be taken into account to estimate diffusivity [96, 99]. However, near the Tg, the amount of free volume is small, so the probability of encountering holes of sufficient size dominates mass transfer. In most cases, when the temperature is lower than the glass transition temperature, the amount of free volume is small and the redistribution of holes within the polymer is negligible because segmental motion is virtually nonexistent.

2.6.5.4 Effect of Drug properties and Preparation process on Polymer characteristics

The biodegradable microspheres and polymer properties are typically and strongly influenced by the preparation process and in certain instances by interactions between the drug and polymer. At times, this may result in faster polymer degradation. For certain drugs, e.g., thioridazine, an amine-catalyzed hydrolysis of the polymer matrix during the particle preparation and a faster release was observed. This was reduced by performing the o/w emulsification at lower temperatures or erasing the drugs nucleophilicity by the formation of a salt. In another study, involving the solid solutions of different amine drugs in PLA, it was shown that an accelerated release correlated well solely with the ability of the respective drug to catalyze the polymer degradation, rather than with the Tg reduction, the drugs pKa, or the drugs octanol-water partition coefficient [110-113].

Contrary to above, the microparticles comprising of a water-soluble acetylated amino acid, N-acetyl cysteine showed an increased catalytic degradation of PLGA (50:50) which was probably associated with a loading-dependent plasticization (Tg reduction). For another drugs, such as haloperidol, the type of matrix erosion changed from bulk to surface-erosion. Furthermore, a faster degradation upon exposure to the release medium was discerned when emulsification is subjected to ultrasound treatment, since it lead to reduction of polymer molecular weight. The suspended solids (s/o dispersion) act as cavitation nuclei, and thus lead to slight augmentation of this phenomenon but presence of dissolved quinine has strikingly more pronounced effect due to amine-catalyzed random chain cleavage of the polymer’s ester bond.

Gamma sterilization of estradiol-loaded microparticles resulted in a loss of polymer molecular weight by random chain scission, a faster release, and the formation of drug degradation products. While a slower release is expected due to trapping of the drug inside the particles especially when hydrophobic drug molecules tend to interact with the polymer matrix either by the hydrophobic binding forces or their amine-groups interact with the polymer carboxyl groups by ionic bonds. An inverse relationship between the release rate and the solid-state solubility of the drug in the polymer has been described for dexamethasone, where an increasing solid state solubility can be observed with end-group capped polymers, higher lactide content, and lower molecular weight of the end capped polymer [111-115].

By contrast, another drug, ketoprofen, dissolves up to 20% in PLGA, forms hydrogen bonds with PLGA, and acts as a plasticizer. This was considered as reason for reduced polymer chain-chain interactions and thus ultimately leading to augmentation of ketoprofen release. However, beside the polymer molecular weight, degradation characteristics, and drug-polymer interactions, there are other significant factors, like the polymer microstructure, that play a key role in the properties of microparticles. For instance, the release of progesterone from PLA vis-a-vis 85/15 PLGA microparticles was found to be faster rather than slower which can be attributed to a rougher surface and higher porosity of the PLA particles. In this specific case, it may be due to the fact that PLA precipitated faster and thus the microparticles were not able to shrink and form the common smooth surface.

On concluding terms the overall inference in accordance to selection of polymer for the development of controlled release biodegradable microparticles include the factors such as biocompatibility and toxicity, degradation rate and time, degradation products, biocompatibility as well as toxicity of the degradation products, chemical, physical, and mechanical properties, processing parameters and requirements, compatibility of the drug with the polymer, required sterilization methods, glass transition temperatures and cost-effectiveness of the biopolymer.

2.6.6 Relevant Properties of Drugs for Microencapsulation and Release

Oral administration is the most sought after mode of administration of dosage forms, since it is typically simple, painless, and dosing of the medication can be easily adjusted or terminated; however in some cases subject to variable bioavailability due to various factors, e.g., food effects may alter drug bioavailability. Taking into consideration, small-molecule drug discovery programs strongly desire compounds with significant oral bioavailability. New compounds are subjected to a screening of key physicochemical parameters, i.e., solubility, polymorphism, pKa, lipophilicity, permeability, and stability [116-119].

The ‘rule of five’ (RO5) is often used to approximate the physicochemical drug properties from the structure. Accordingly, it can be propounded that poor absorption and permeability are more likely when one or more of the following criteria are satisfied: the calculated logarithmic octanol–water partition coefficient (cLogKp2) is >5, the molecular weight (Mw) is >500, there are more than 5 H-bond donors, or 10 H-bond acceptors in the molecule. Furthermore, two more aspects interrelated with the RO5 criteria viz a lower polar surface area (sum of polar atoms including H-bond donors and acceptors) and a reduced flexibility of the molecule (less rotatable bonds, as typically observed for lower Mw drugs) are also considered to be a good predictors for oral bioavailability. Drifting away from easy oral delivery, there is a rising trend towards discovery of new chemical entities with larger molecular weight and/or larger lipophilicity obtained by medicinal chemistry. Also, it must be emphasized that simply abiding or showing violations to RO5 does not guarantee certain properties of interest (drug-like vs. non-drug-like) such as high or low oral bioavailability or target selectivity, respectively, for a specific chemical entity. However, there is a high propensity that new drugs considered for parenteral application in a microparticle formulation will show physicochemical properties that may contravene either one or more of the RO5 criteria [114, 116-118].

Besides physicochemical properties, the pharmacokinetics of the drug, i.e., its absorption, distribution, metabolism, and excretion (ADME), needs to be pondered upon while discussing bioavailability. The absorption of small hydrophobic molecules is often related to their physicochemical properties that include drug dissolution from the (oral) formulation (dissolution rate vs. retention time in the intestine), drug solubility, and drug permeability (passive diffusion is a main mechanism for lipophilic compounds, but might be limited by high Mw). The biochemical barrier serves the biological function to reduce potential toxicity from xenobiotics by hepatic and intestinal first-pass metabolism as well as intestinal efflux transporters such as P-glycoprotein (Pgp), which may reduce bioavailability and, in turn, raise microencapsulation candidates that potentially have passed the RO5. However, there is some likelihood that drug conformity with a RO5 subset (Mw< 400, H-bond acceptors <4, and certain ionization features) will result in drug candidates that are not substrates of Pgp [113, 115].

Finally, low-dose drugs that show good oral bioavailability are worth considerable for encapsulation and controlled release from, injectable microparticles if: (a) a more constant plasma concentration is sought than obtained when administered orally, (b) a local delivery is preferred, (c) the drug is indicated for the long-term treatment of diseases often associated with a low compliance, e.g., narcotic addiction or certain neurological disorders, (d) if the embedding into microparticles will help to stabilize or target the drug or (e) it would be more convenient to have a shot every couple months than following daily administration schedules.

2.6.6.1 Solubility of drug in Aqueous and Organic media

The term "hydrophobic drugs" refers to a heterogeneous group of molecules that have poor solubility in water and that are usually, but certainly not always, soluble in various organic solvents. Such substances are frequently categorized as slightly soluble (1-10 mg/ml), very slightly soluble (0.1-1 mg/ml), and practically insoluble (<0.1 mg/ml). Steroidal drugs belong to class of poorly water soluble drugs; however, their aqueous solubility varies over at least two orders of magnitudes. Further, even lower aqueous solubility usually in range of a few ng/ml is also exhibited by some of the hydrophobic drugs. The high-throughput screening of kinetic and thermodynamic solubility as well as the prediction of solubility is of major importance in discovery (lead identification and optimization) and development because undesirable pharmacokinetic properties usually accompany the inadequate solubility [111-117].

The determination of drug solubility in aqueous media is imperative in the initial phase of every microencapsulation study since microparticles are most often prepared by emulsion techniques that include aqueous phases. In emulsion-based encapsulation techniques the external phases are commonly aqueous solutions predominantly containing polyvinyl alcohol (PVA) as the emulsifier. The pH dependency of the solubility needs to be carefully characterized in the case of ionizable drugs. This can be performed by micro solubility methods that can address the limited availability of drug and moreover, these have shown good agreement with conventional assays. [113-116].

Moreover, the drug solubility should also be determined in presence of excipients, e.g., Tween® 20 or Tween® 80 non-ionic surfactants since these are often used in release buffers like PBST (phosphate buffered saline + Tween® surfactant). Since, most of the microencapsulation techniques employ volatile organic solvent to dissolve the matrix polymer and/or the drug as well so it is obligatory to determine the drug solubility in common organic solvents like methylene chloride, acetonitrile and ethyl acetate, also in potential co-solvents like methanol, ethanol, acetone, and tetrahydrofuran and in the solvent mixtures. Thus, the outcomes of solubility studies ultimately form the rationale for the selection of appropriate encapsulation technique [117-120].

The octanol-water partition coefficient Kp is indicator of lipophilic/hydrophilic nature for new molecules which is either calculated or determined experimentally. The behavior of drug in biological systems and its relative distribution in two-phase solvent systems can be predicted by Kp. Since,