ABSTRACT:
Asphalt is the preferred advanced construction material for modern construction of all forms of roadways. Asphalt continues to advance in its ability to adapt to a wide variety of loads and climatic conditions. However, since asphalt is the chosen material, it is very widely used across the nation. This results in numerous modes of failure for asphalt since every construction site is unique. Some of the forms of failure that have been classified are: fatigue cracking, bleeding, block cracking, corrugation and shoving, depression, joint reflection cracking, longitudinal cracking, patching, polished aggregate, potholes, raveling, rutting, slippage cracking, stripping, transverse (thermal) cracking, water bleeding and pumping. These failures occur for numerous conditions and can be caused due to another failure which are explained in this paper. Many of the failures occur from the same cause and create the same type of hazardous condition. However, much of the failures produce unique problems that another failure can not cause, these failures are easier to recognize but are usually less common.

INTRODUCTION:
What are asphalt failures? How do asphalt failures occur? And why do asphalt failures occur? Any observer of any modern day constructed roadways may ask themselves these questions. A bystander may believe that those cracks observed on roadways to be due to just traffic, however, this is not the only contributor to asphalt damage, but only one possible factor. Asphalt, or pavement failure occurs when the surface of the asphalt can no longer maintain its initial shape and develops a material stress which causes various forms of damage 1. Doing some research into asphalt failures, one can easily find that “pavement failure is caused by a number of variables including water, intrusion, stress from heavy vehicles, expansion and contraction from seasonal changes, as well as sun exposure” 1. The most common and basic forms of asphalt failure include, cracking, distortion, disintegration, skidding hazards and surface treatment distress. These asphalt failures are just a few of the many forms of failures that are affecting the commute on the roadways to date.

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DISSCUSSION:
As presented previously, there are many forms of asphalt distress which include fatigue cracking, bleeding, block cracking, corrugation and shoving, depression, joint reflection cracking, longitudinal cracking, patching, polished aggregate, potholes, raveling, rutting, slippage cracking, stripping, transverse (thermal) cracking, water bleeding and pumping.
Fatigue cracking
Fatigue, or also known as alligator, cracking is a series of interconnected cracks caused by fatigue of the hot mix asphalt (HMA) surface under a repeated traffic loading. As the asphalt reaches its maximum limit of loads, longitudinal cracks begin to form starting in the wheel paths where the pavement experiences the most friction and load. “After repeated loading, these longitudinal cracks connect forming many-sided sharp-angled pieces that develop into a pattern resembling the back of an alligator or crocodile” 2. This causes a roughness on the surface of the pavement that is an indicator of structural failure. Furthermore, these cracks also allow infiltration of moisture into the base and subgrade levels which will eventually result in other issues such as potholes, and if left untreated, pavement disintegration will occur. Some common possible causes of poor structural support are a decrease in load supporting properties such as a loss of base, subbase or subgrade support due to inadequate drainage. “Water under a pavement will generally cause the underlying materials to become weak” 2. Also, an increase in loading where the asphalt is loaded heavier than its design, inadequate structural design where the asphalt was designed too thin for the anticipated loads, or possibly poor compaction during construction are all possible causes of inadequate structural support 2. The figure below represents severe fatigue cracking near the stop line at an. intersection.
Figure 1: Fatigue (Alligator) Cracking

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Bleeding
Another form of asphalt failure is called bleeding. Bleeding is when a film of asphalt binder creates a shiny, glass-like reflecting surface that usually becomes sticky when dry and slippery when wet due to a loss of skid resistance. Some possible causes of bleeding are when an asphalt binder fills the voids of the aggregate during either hot weather or compaction due to traffic, and then spreads onto the surface of the asphalt. Bleeding is nonreversible, so during periods of low temperatures or loading, the binder will accumulate over time on the asphalt surface. The most likely causes of bleeding include an excesses of asphalt binder in the HMA either due to a poor mix design or manufacturing issue. Another cause is a low HMA air void content where there is not enough void space for the asphalt to occupy due to a problem in the mix design 2. The figure below represents a severe case of bleeding.
Figure 2: Bleeding

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Block Cracking
Block cracks are interconnected fractures that divide the asphalt up into rectangular blocks range in size from approximately one square foot to one hundred square feet. Blocks larger than one hundred square feet are generally classified as longitudinal and transverse cracking. Although, block cracking normally occurs over a large portion of pavement area, sometimes it will occur only in non-traffic areas 2. This cracking, like fatigue cracking, allows the infiltration of moisture and causes excess roughness as well. Some possible causes of block cracking are due to HMA shrinkage and daily temperature cycling. Or more typically is caused by an inability of asphalt binder to expand and contract with temperature cycles due to aging or poor choice of binder in the initial mix design 2. The figure below represents block cracking in a parking lane that most likely experiences little traffic.
Figure 3: Block Cracking

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Corrugation and Shoving
Corrugation and shoving are both other forms of asphalt failures where plastic movement occurs and is characterized by ripples, as known as corrugation, or by abrupt waves, as known as shoving, through the surface of the pavement. The deformation is typically perpendicular to the direction of traffic and occurs at points where the traffic usually begins and ends (i.e. corrugation) or areas where the HMA meets a rigid object (i.e. shoving) 2. This creates an excess of surface roughness, that can eventually lead to more major damage. Corrugation and shoving are commonly caused by actions due to traffic (e.g. starting and stopping) combined with other factors such as an unstable (i.e. low stiffness) HMA layer possibly caused by mix contamination, poor mix design, poor HMA manufacturing, or lack of aeration of liquid asphalt emulsions. Traffic can also be combined with an excess of moisture in the subgrade layer to cause corrugation and shoving 2. The figure below represents shoving and corrugation at a high-profile intersection.
Figure 4: Shoving/Corrugation

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Depressions
Another asphalt failure are depressions, which are localized pavement surface areas with slightly lower elevations than the surrounding surfaces. Depressions can easily be observed when precipitation has occurred, and the depressions have filled with water. Depressions can cause problems such as excess roughness, or worse, when the depressions fill with water, they can cause vehicle hydroplaning. Depressions are caused by a settlement of the subgrade layer resulting from inadequate compaction during the construction phase 2. The figure below depicts depression that has caused fatigue cracking in an access roadway most likely caused by subgrade settlement.
Figure 5: Depression

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Joint Reflection Cracking
Joint reflection cracking are the cracks in a flexible overlay of rigid pavement. These cracks will occur directly over the underlying rigid pavement joints. However joint reflection cracks do not include reflection cracks that occur away from an underlying joint or from any other type of base such as cement or lime stabilized 2. Problems that arise from this failure include moisture infiltration and excess roughness. A possible reason that joint reflection cracking has occurred is due to the movement of the rigid pavement slab beneath the HMA surface due to thermal and moisture changes. Although loading does not initiate this failure, it can increase rate by which the cracking occurs 2. The figure below represents joint reflection cracking on an urban roadway.
Figure 6: Joint Reflective Cracking

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Longitudinal Cracking
Another form of fatigue cracking is classified as longitudinal cracking, where the cracks are parallel to the pavement’s centerline or laydown direction. Problems that exist due to longitudinal cracking include moisture infiltration and roughness. These issues are indicative that an onset of fatigue cracking and possibly structural failure 2. During the construction phase, if the joints are placed in the wheel path or are initially constructed poorly, they will most likely fail early. This is because the joints are typically the least dense areas of the pavement, so therefore, the joints typically constructed away or outside of the wheel paths to prevent an excess of loading. Furthermore, reflective cracking can also cause longitudinal cracks from the underlying layer along with HMA fatigue, which as mentioned before indicates an onset of future fatigue cracking, and top-down cracking 2. The figure below represents longitudinal cracking that appears to be onset of fatigue cracking and is most likely occurring on the longitudinal joints.
Figure 7: Longitudinal Cracking

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Patching
Another form of asphalt distress is patching. Although patching is a form of pavement repair, it actually is considered a failure. Patching is “an area of pavement that has been replaced with new material to repair the existing pavement. A patch is considered a defect no matter how well it performs” 2. Patching, amongst other issues that will eventually arise with aging and deterioration, casues an excess of roughness. This failure is caused by previous localized pavement erosion that has been cut and removed from area and replaced with fresh asphalt known as the patch. The figure below displays a large utility patch across a roadway where the edges of the patch are separated from the existing pavement.
Figure 8: Patching

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Polishing
Polished aggregate are areas of HMA pavement where a portion of the aggregate that is in contact with the above asphalt binder is either very small or there are no rough or angular aggregate particles. Since there is less resistance due to friction polished aggregate causes a decrease in skid resistance. As the pavement ages, the protruding rough, angular aggregate particles become polished as they are more susceptible to abrasion due to repeated traffic 2. The figure below depicts a pavement surface where the aggregate has experienced wear for about five years.
Figure 9: Polishing

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Potholes
Potholes are one of the more common types of asphalt failures experienced by drivers. Potholes are small to large, bowl-shaped depressions in the surface of the pavement that penetrate all the way through the HMA layer down to the base course. Typically, potholes have sharp edges and the sides are vertical near the surface of the hole where the asphalt has been stripped away. Potholes are most likely to occur on roads with a thin HMA surface of about one to two inches rather than on a road constructed with a four inch or more HMA surface 2. Potholes cause many issues such as roughness and moisture infiltration with the more serious problem being the damage caused to vehicles driving across potholes at high speeds. Furthermore, potholes are commonly caused by untreated fatigue cracking once it has become more severe and the interconnected cracks create disconnected wedges in the pavement. As vehicles drive over these small wedges, they become dislodged and the remaining hole is called the pothole 2. The figure below represents potholes that have formed on a major highway.
Figure 10: Potholes

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Raveling
Another asphalt failure is called raveling, which is “the progressive disintegration of an HMA layer from the surface downward as a result of the dislodgement of aggregate particles” 2. Raveling causes problems such as loose debris on the surface of the pavement, roughness, water collection in raveled locations that can result in hydroplaning, and loss of skid resistance. Raveling is a fairly common failure of asphalt and hence has many possible causes. A loss of bond between aggregate particles and the asphalt binder as a result of aging where oxidation of the asphalt binder as occurred. As the binder ages, “oxygen reacts with its constituent molecules resulting in a stiffer, more viscous material that is more likely to lose aggregates on the pavement surface as they are pulled away by traffic” 2. A loss of bond can also occur due to a dust coating on aggregate particles that causes the asphalt binder to attach to the dust particles rather than the aggregate. Aggregate segregation can also cause a loss of bond if the aggregate mixture is gap-graded and the fine particles are missing from the matrix, then the asphalt binder has no other option but to bond with the remaining coarse particles that contain few points of contact. Loss bond between the aggregate and binder due to inadequate compaction during construction. A high density is required by the HMA in order to develop a sufficient cohesion and poor compaction can actually cause rutting because once the pavement begins experiencing traffic, compaction will continue in the wheel paths due to the new loading. Raveling can also be caused by a variety of mechanical devices such as snow plows, studded tires or vehicles with tracks 2. The figure below displays a section of roadway that has experienced raveling due to segregation, temperature differentials or poor compaction.
Figure 11: Raveling

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Rutting
Rutting is a form of asphalt failure where surface depressions form in the wheel paths. Along the sides of the rut, a pavement uplift may occur due to shearing. Ruts are easily observed after rain and the ruts have filled with water. There are two forms of rutting, mix and subgrade. Mix rutting occurs when the subgrade does not rut yet and the pavement surface exhibits wheel path depressions due to compaction or mix design issues. On the other hand, subgrade rutting occurs when the subgrade exhibits the wheel path depressions due to traffic loading and the pavement settles into the subgrade ruts causing the surface depression 2. As mentioned in previous failures in any location where water can collect and puddle, vehicle hydroplaning can occur which is the case for rutting. Ruts also tend to pull vehicles towards the rut path as it is steered across the path causing a very hazardous condition. Rutting is generally caused by a “permanent deformation in any of a pavement’s layers or subgrade usually caused by consolidation or lateral movement of the materials due to traffic loading” 2. Some specific cases that cause rutting include inadequate compaction during construction in which compaction continues after it is opened, subgrade rutting or a defective mix design. The figure below depicts rutting at a busy intersection in region of high heat.
Figure 12: Rutting

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Slippage Cracking
Another form of asphalt failure is slippage cracking. Slippage cracks are crescent or half-moon shaped cracks typically having two ends extended unto the direction of traffic 2. Problems that arise from slippage cracking are moisture infiltration and an excess of surface roughness. Slippage cracking is commonly caused by braking and wheel turning which causes the pavement surface to slide and deform. This sliding and deformation are “caused by a low-strength surface mix or poor bonding between the surface HMA layer and the next underlying layer in the pavement structure” 2. The figure below represents a slippage crack that was most likely caused by an inadequate bonding of the tack coat.
Figure 13: Slippage Cracking

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Stripping
Stripping is classified as the loss of bond between aggregates and asphalt binder that commonly begins at the bottom of the HMA layer and advances upwards. Raveling as mentioned previously is when the stripping begins at the pavement surface and moves downward. Problems that persist due to stripping include decreased structural support, rutting, shoving and corrugation, raveling, fatigue and longitudinal cracking. “Bottom-up stripping is very difficult to recognize because it manifests itself on the pavement surface as other forms of distress including rutting, shoving/corrugations, raveling, or cracking” 2. Usually a sample of the core must be collected to properly identify this type of asphalt distress. Stripping is commonly caused by an inadequate aggregate surface chemistry and water in the HMA that causes moisture damage. The figure below displays small asphalt core showing stripping at the bottom of the pavement section.
Figure 14: Stripping

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Transverse (Thermal) Cracking
Another asphalt failure is transverse or thermal cracking which are cracks that form perpendicular to the pavement’s centerline or laydown direction. Transverse cracking allows moisture infiltration and roughness. “Shrinkage of the HMA surface due to low temperatures or asphalt binder hardening, reflective crack caused by cracks beneath the surface HMA layer and top-down cracking” are all possible causes for thermal cracking 2. The figure below represents a transverse crack during a winter season when the temperature is very low.
Figure 15: Transverse (Thermal) Cracking

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Water Bleeding and Pumping
When water seeps out of joints or cracks or though an excessively porous HMA layer that is known as water bleeding. Pumping occurs when water and fine material is ejected from underlying layers though cracks in the HMA layer or out the sides of the HMA layer under moving loads 2. Water bleeding and pumping cause issues such as decreased skid resistance and structural support for pumping while water bleeding is an indication of high pavement porosity. Possible causes for this failure include pavement containing high porosity due to poor compaction, a high-water table or poor drainage 2. The figure below depicts water bleeding/pumping though a porous pavement surface.
Figure 16: Water Bleeding/Pumping

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CONCLUSION:
The knowledge of all forms of asphalt failures is important to understanding how pavement reacts to different conditions. This information can help engineers to design for each unique condition to prevent the same failures from happen once they have been replaced or repaired. A successful asphalt mixture and proper regular maintenance is the key to preventing failures on new and existing roadways. With annual maintenance and inspections roadways will never experience any severe damage, however, with an ever-growing society, more mileage of asphalt is being laid everyday which is decreasing the overall quality of all roadways. This due to the fact that there is just too much roadway to constantly check and maintain. In other words, the rate of asphalt failure is greater than the rate that the asphalt is being repaired. So, when one road is repaired, most likely one or more other roads are reaching severe conditions and require repair or even complete replacement. Although an excellent asphalt design can last years, it will not last for eternity and will require maintenance and replacement many times throughout the roadway’s lifetime.

Abstract: In recent theories of language use, a distinction is made between the meaning of an uttered sentence, the semantics, and the enriched meaning of its utterance, the pragmatics. The latter is supposed to be systematically underdetermined by the former. One strategy to bridge the gap between the semantic and the pragmatic side of the utterance is to assume unarticulated constituents which are understood by the addressee. I argue that this strategy is problematic because the choice of the correct unarticulated constituent is underdetermined itself. A proposal is made for capturing the relation between the semantic and the pragmatic side of the utterance by means of the notion of a pragmatic template. It is understood as a holistic structure of context elements which are assumed by addressees in order to enrich semantically underdetermined utterances.
If someone is asking me
(i) “Do want to eat anything?” and I reply
(ii) “I’ve had breakfast”,
we mutually assume that my utterance means that I’ve had breakfast today, and my addressee infers from this that I don’t want to eat anything at the moment. The reason for this is that, if I am uttering a sentence like (ii) in a verbal interchange, nobody assumes that solely the uttered signal is relevant for the interpretation of the utterance. Instead, the participants of the verbal interchange will go beyond the words they hear (or read) and enrich the perceived utterance so that they are able to grasp what was obviously meant. In recent theories of language use, this very common fact has been reflected by developing a number of categories which all serve the purpose of distinguishing the meaning of the uttered sentence, its ‘semantics’ – which in case of (i) only says that S has had breakfast once in his life – from the enriched meaning of the utterance itself, its ‘pragmatics’ – which adds a temporal restriction of the breakfast. In my contribution, I want to reflect on this distinction and I shall make a proposal concerning the nature of these enrichments leading to the pragmatic interpretation.
What is articulated – what is expressed
Terminologically, I distinguish between what is articulated (pure sentence meaning, ‘semantics’) and what is expressed by a speaker with his or her utterance (complete utterance meaning relying on relevant context-information, ‘pragmatics’). In everyday conversation as a rule only part of what is expressed is also articulated (s. example (ii)). Many if not most recent theories assume that these parts which are expressed but not articulated are nevertheless part of the utterance as an unarticulated constituent (e.g. a single word like today). I want to demonstrate that this strategy gives rise to severe problems of description and finally cannot be maintained. One of the problems is that usually a lot of unarticulated constituents are good candidates for having been meant by the speaker, and we are not able to decide which of them exactly was expressed. From this and other problems follows that we should not assume unarticulated constituents hidden in the uttered sentence, but only articulated ones overtly coded in the sentence.
I shall argue for an alternative account which sees unarticulated information outside the uttered sentence, as part of the background of the respective utterance. I suggest a conception which sees the relevant information responsible for the reading of today as part of the language game in which utterances like (ii) are performed. In our example the background is a culturally shared practice concerning regular meals which is known by the participants of the verbal interchange. Thus the strategy of assuming unarticulated constituents has to be replaced by the strategy of assuming rich language games in which the respective utterances are embedded. In my proposal, these language games are called pragmatic templates.
As to the (short) tradition of semantic / pragmatic reasoning, the level of what is expressed but not articulated has been categorized differently: It has been dubbed unarticulated constituent (Perry, Récanati), explicature (Sperber/Wilson, Carston), impliciture (Bach), the Austinian proposition (Barwise, Récanati). I begin with a discussion of the concept of unarticulated constituents as formulated by Perry and Récanati, and then pass on to the concept of an Austinian proposition (Barwise, Récanati). After this, I try to clarify the concept of pragmatic templates and give further explanations of the related term of the central use which is a core notion of pragmatic templates. Finally, I present arguments which demonstrate that by means of pragmatic templates one may explain at least some central cases of language use better than by means of unarticulated constituents.
Unarticulated constituents
One example of an utterance containing allegedly unarticulated constituents was already given. Further examples are:
(iii) It is raining.
(iv) They are serving drinks at the local bar.
In order to understand (iii) or (iv), we must know where the speaker is and which place is meant. So these sentences could be paraphrased as follows:
(iii’) It is raining here.
(iv’) They are serving drinks at the bar near here. (see Perry 1998)
The expressions here and near here are unarticulated constituents of (iii) and (iv). However, these paraphrases are not always valid because it is possible that (iii) or (iv) refer to places different from where the speaker is – then it has to be there or near you. An appropriate localisation depends on the intention of the speaker. In any case, a constituent must be added to what is said to assign a truth value to the proposition. This constituent must be supplied by the context because the sentence does not contain a morpheme carrying the necessary information. Perry writes: “… we don’t articulate the objects we are talking about, when it is obvious what they are from the context” (Perry 1998: 11).
F. Récanati who develops Perry’s notion of an unarticulated constituent further, makes a distinction between two sorts of consequences, when one or more constituents are not articulated. Either the utterance is vague, so that information has to be added to determine the fact the speaker is talking about, or the utterance is incomplete, so that information has to be added to identify the fact at all (see Récanati 2002: 307 f.) The first type (the A-type) occurs in those cases Récanati gives as example of unarticulated constituents. It contains the types of usage which are given as examples in pragmatic literature since Sperber and Wilson. Beneath our breakfast example, we have:
(v) Mary took out her key and opened the door,
in which case it is expressed that Mary managed to open the door with this very key.
The second type of unarticulated constituents (the B-type) contains cases in which facts cannot be identified without the unarticulated constituent, which means that no proposition has been expressed. This is given in the case of the rain-example: No truth value can be assigned to the proposition without occupying the argument role of the place. It is decisive for Récanati’s further argumentation to ignore unarticulated constituents of the B-type – they are irrelevant for the question how much pragmatic information a proposition must contain to be assigned with a truth value.
If unarticulated constituents are only those which are not triggered by an expression within the sentence, pragmatic saturations (mandatory expansions in his terms) cannot be (or at least only in the weak sense) cases of unarticulated constituents. Thus, the only possible candidates for unarticulated constituents are free enrichments (optional expansions in his terms).
Récanati uses a very restricted concept of unarticulated constituents. If an argument within the propositional structure is not filled (e.g. She finishes _), this signals that the constituent is not really unarticulated. Only if the proposition does not contain an empty argument place (e.g. She eats in the intransitive sense), we can call it unarticulated, and we may speak of pragmatic enrichment if we want to add what she eats. Récanati sums up his position in a subheading: “True Unarticulated Constituents are Never Mandatory” (2002: 313). The decisive question is however: Why should addressees enrich an expression by means of adding an unarticulated constituent – which means that they have higher processing costs – if the speaker has chosen an expression which doesn’t contain this argument (intransitive sense of to eat). He or she seems to have reasons to choose an intransitive version and not the transitive one: It may be relevant that a person eats, but completely irrelevant, what she eats. So enriching the utterance in this case is pointless.. The principle that unarticulated constituents are never mandatory seems to conflict with the idea of the rational choice of verbal means for communicative purposes.
Austinian propositions
In his book ‘Perspectival Thought’ (2007), Récanati uses a different terminology for determining the role of unarticulated constituents. He distinguishes between the explicit content of an utterance which he dubs with a stoicist term the lekton, and the complete content of that utterance, which is called the Austinian proposition (after J. Barwise 1989). The complete content of the Austinian proposition encompasses the circumstance of evaluation in which the utterance has been performed – or, in terms of Perry, the situation the utterance concerns (s. Perry 1986). Following Récanati, utterances like (iii) are context-sensitive because the (explicit) content, which is called the lekton, is evaluated with respect to varying circumstances. The result of this strategy is that we have three levels of meaning of an utterance: the meaning of the sentence type , the context-dependent lekton and the Austinian proposition. Concerning the third level, it contributes to the truth conditions of the uttered sentence, i.e. it is true or false concerning the respective circumstance of evaluation. Consequently the locus for unarticulated constituents is not the lekton, but the Austinian proposition, the circumstance of the utterance which co-determines its truth-value: “… there are no unarticulated constituents in the lekton – all unarticulated constituents belong to the situation of evaluation.” (Récanati 2010, 23).
If one conceives of the items of the environment of an utterance as constituent parts of an (Austinian) proposition, as Récanati does, they are something what-is-said by an utterance, analogous to free pragmatic enrichments, at least as I understand these notions (s. Récanati 2010 cites the critique of Kölbel 2008 in this respect). So in my view there does not exist a fundamental difference between the 2002 account of unarticulated constituents (in which they are part of what is said, i.e. free pragmatic enrichments) and his 2007 / 2010 account (in which they are part of the Austinian proposition, external to the lekton). To put it in another way: the borderline between the lekton and the Austinian proposition is underdetermined, it reduces eventually to the older distinction between the meaning of the sentence on the one hand and free pragmatic enrichments on the other. Also in the new account, unarticulated constituents are not really excluded from the realm of what-is-said. The information belonging to unarticulated constituents is not part of what-is-said, it isn’t anything which might be part of a single proposition wherever it might be located in the architecture of an utterance. Rather it is “outside” from the utterance, “outside” from what-is-said or an Austinian proposition. It isn’t anything speakers mean and addressees grasp, but it is part of a type of knowledge addressees make use of if they are going to interpret what might have been meant with the utterance. And this is exactly what speakers presume if they choose their words.
Pragmatic templates
In the following section, I will give some reasons in favour of the conception that the information which speakers do (sometimes) not articulate in their utterances, although they want the addressee to get that information, should not be represented as part of the utterance. It is nothing the speaker says. It is rather something the addressee hypothetically assumes or already knows, which thus does not need to be articulated because it can be derived from the context. The speaker is calculating with this knowledge, it is part of the “nonlinguistic infrastructure” (see Tomasello 2008) to which speaker and addressee are referring. Now we have to explain what that something is that can be derived from the context.
The rational usage of linguistic means in utterances is subject to certain conditions, which restrict their usage. These conditions may not be represented as an unsorted collection of constraining propositions, but they form structured clusters of conditions of usage. They contain the obligatory context elements in which a certain expression can be used appropriately. These clusters are a part of what I call pragmatic templates. If we want to identify such a template, we have to assign the utterance to a specific type (form type). We also have to be able to give criteria of what is part of a template and what is not. I propose to consider the content of pragmatic enrichments or unarticulated constituents as a part of such a pragmatic template – it is part of the knowledge of language users which is activated when they hear or read an utterance in which not everything is articulated that could be relevant in that situation.
The notion of a pragmatic template has some ancestors, e. g. the notion of a “language game” (Wittgenstein PI: § 23), or that of a “script” as a device for handling “stylized everyday situations” (Schank and Abelson 1975: 151). The common trait of the notion of a pragmatic template with its ancestors is the fact that a set of properties or entities forms a structured whole with characteristic features which is acquired and used as a linguistic or semiotic unit together with pragmatic factors of its use. If an expression is used in accordance to the stereotypical pragmatic template, I speak of its central use (borrowing from Grice’s notion of a central speech act, s. Grice 1989). The notion of a central use, roughly speaking a use the type of utterance is made for, has some analogies to the term “proper function”, which Millikan used on a different theoretical background (see Millikan 2004).
I am of the opinion that utterances of sentences such as (ii) and related ones can be interpreted correctly because of their assignment to a relevant template. When we interpret an utterance in using a pragmatic template, we trace it back to an acquired holistic structure of characteristics of the environment it is used in. We do not have to add an unarticulated constituent in every situation, but we can use our standardised conversational knowledge. That knowledge provides us with prototypical applications (the central use) of specific types of utterances. Of course there are always parts of the meaning related to the situation that have to be represented ad hoc. But I claim that a major part of the interpretation can be accomplished by identifying a type of utterance as part of a specific pragmatic template.
The central concern of my contribution is that items like today, here etc. are not unarticulated constituents which have to be adjoined to the articulated part of the utterance. Rather this additional information is gained through the situational context or our world knowledge, and my aim was to show that a systematic account of this connection of utterance type and situation type is possible along the lines of pragmatic templates.

ABSTRACT:
The microemulsion systems, o/w, composed of castor oil, sesame oil, arachis oil, olive oil, polysorbate 20, polysorbate 80, Tyloxapol, Carbomer 974P, carboxymethyl cellulose sodium, hydroexthylecellulose, glycerine, propylene glycol, sodium chloride and purified water, taken at various amounts and in various combinations, were tested in order to assess their physical-chemical compatibility. All ingredients of the microemulsions were physiologically acceptable. Microemulsions were evaluated for the different parameters to access the effect of processing parameters on the globule size formation and stability. The stable microemulsion system was obtained for the formulation in which castor oil and polysorbate 80 was used.. The following parameters were analyzed: description, pH, osmolality, viscosity, specific gravity, globule size, polydispersity index (PDI)
zeta potential, surface tension, assay, in vitro Drug Release. The study made it possible to select the most stable microemulsion system meeting the requirements of eye drops. Thus the proposed formulation and process were successfully developed and evaluated.

KEYWORDS: Microemulsion, Surfactant, Drug solubilizing agent, Homogenization, globule size

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INTRODUCTION:
Overview of Ophthalmic drug delivery
Ophthalmic drug delivery is one of the most interesting and challenging endeavors facing the pharmaceutical scientist. The anatomy, physiology, and biochemistry of the eye render this organ highly impervious to foreign substances. A significant challenge to the formulator is to circumvent the protective barriers of the eye without causing permanent tissue damage. Development of newer, more sensitive diagnostic techniques and novel therapeutic agents continue to provide ocular delivery systems with high therapeutic efficacy. Potent immunosuppressant therapy in transplant patients and the developing epidemic of acquired immunodeficiency syndrome have generated an entirely new population of patients suffering virulent uveitis and retinopathies. Conventional ophthalmic solution, suspension, and ointment dosage forms no longer constitute optimal therapy for these indications. Research and development efforts to design better therapeutic systems particularly targeted to posterior segment are the primary focus of this text. The goal of pharmaco-therapeutics is to treat a disease in a consistent and predictable fashion. An assumption is made that a correlation exists between the concentration of a drug at its intended site of action and the resulting pharmacological effect. The specific aim of designing a therapeutic system is to achieve an optimal concentration of a drug at the active site for the appropriate duration. Ocular disposition and elimination of a therapeutic agent is dependent upon its physicochemical properties as well as the relevant ocular anatomy and physiology1. A successful design of a drug delivery system, therefore, requires an integrated knowledge of the drug molecule and the constraints offered by the ocular route of administration. The active sites for the antibiotics, antivirals, and steroids are the infected or inflamed areas within the anterior as well as the posterior segments of the eye. Receptors for the mydriatics and miotics are in the iris ciliary body. A host of different tissues are involved, each of which may pose its own challenge to the formulator of ophthalmic delivery systems. Hence, the drug entities need to be targeted to many sites within the globe.
Historically, the bulk of the research has been aimed at delivery to the anterior segment tissues. Only recently has research been directed at delivery to the tissues of the posterior globe (the uveal tract, vitreous, choroid, and retina).

Ophthalmic microemulsion
For the treatment of different extra- and intra-ocular aetiological conditions such as glaucoma, uveitis, keratitis, dry eye syndromes, cytomegalovirus retinitis, acute retinal necrosis, proliferative vitreo retinopathy, macular degenerative disease, etc. a lot of lipophilic and poorly water soluble drugs have become available in recent years. However, most of the traditional ophthalmic dosage forms are clearly not only uncomfortable for the patient, but also not efficient in combatting some of the current virulent ocular diseases. Furthermore, in ophthalmology, the low viscosity topical formulations either in aqueous-based eye drops or in liquid retentive suboptimal forms are generally preferred to provide local drug concentrations in the precorneal or aqueous humor part of the eye.
In the last decade, oil-in-water (o/w) type lipid emulsions, primarily intended for parenteral applications, have been investigated and are now exploited commercially as a vehicle to improve the ocular bioavailability of lipophilic drugs2, 3, 4.

Figure 1: Anatomical structure of the human eye.
Oil and water are immiscible. They separate into two phases when mixed, each saturated with traces of the other component5 . An attempt to combine the two phases requires energy input to establish water-oil contacts that would replace the water-water and oil-oil contacts. The interfacial tension between bulk oil and water can be as high as 30-50 dynes/cm6 . To overcome this, surfactants can be used. Surfactants are surface-active molecules. They contain water-loving (hydrophilic) and oil-loving (lipophilic) moieties7. Because of this characteristic, they tend to adsorb at the water-oil interface. If enough surfactant molecules are present, they align and create an interface between the water and the oil by decreasing the interfacial tension5. An emulsion is formed when a small amount of an appropriate surfactant is mechanically agitated with the oil and water. This results in a two-phase dispersion where one phase exists as droplets coated by surfactant that is dispersed throughout the continuous, other phase. These emulsions are milky or turbid in appearance due to the fact that the droplet sizes range from 0.1 to 1 micron in diameter6. As a general rule, the type of surfactant used in the system determines which phase is continuous. If the surfactant is hydrophilic, then oil will be emulsified in droplets throughout a continuous water phase. The opposite is true for more lipophilic surfactants. Water will be emulsified in droplets that are dispersed throughout a continuous oil phase in this case8.
Emulsions are kinetically stable, but are ultimately thermodynamically unstable. Over time, they will begin to separate back into their two phases. The droplets will merge together, and the dispersed phase will sediment (cream) 6. At this point, they degrade back into bulk phases of pure oil and pure water with some of the surfactant dissolved in preferentially in one of the two5.
From the extensive literature cyclosporine was selected for the study as it has poor water solubility and is highly lipophilic in nature. Cyclosporine is a white crystalline powder with chemical formula C62H111N11O12 and molecular weight of 1202.6. Cyclosporine is Soluble in ethanol and DMSO.

Figure 1 Chemical structure of Cyclosporine

MATERIAL AND METHODS:
Chemicals and reagents:
Cyclosporine API was received as gift sample from Concord biotech, India. Carbomer 974P was received as gift sample from Aqualon and Carboxymethylcellulose sodium and Hydroxyethylcellulose was received as gift sample from Ashland. Polysorbate 20 and Polysorbate 80 were purchased from Merck chemicals. Tyloxapol was received as gift sample from Amri renseller. All chemicals and reagents used were analytical grade unless otherwise indicated.

Instrumentation:
A variety of techniques can be used to characterize microemulsions. In the present study, microemulsions were characterized using dynamic light scattering, polarized light microscopy, zeta potential, surface tension, pH, osmolality, viscosity, drug assay and in vitro drug release. The each technique used for the test parameter determination is given as below,
Table 1: List of instruments and techniques used
Sr. no. Technique name Instrument name and model Parameter tested
1 Dynamic light scattering Zetasizer nano ZS (Malvern) Globule size and polydispersity index
2 Polarized light microscopy Microscope and TEM Morphology
3 Zeta potential Zetasizer nano ZS (Malvern) Zeta potential
4 Du Nouy ring method Tensiometer K100 (Kruss GmbH, Germany) Surface tension
5 pH measurement pH meter (Thermo) pH
6 Tonicity measurement Osmomter (Osmomat) Osmolality
7 Viscosity measurement Brookfiled viscometer (DV+ Pro) Viscosity
8 Drug assay HPLC (Agilent) with UV detector Assay
8 Dissolution Franz diffusion cell In Vitro drug release
9 High shear homogenization High Shear mixer/homogenizer (Ultraturex IKEA) For primary emulsion formation
10 High pressure homogenization High pressure homogenizer (Panda –Nero Soavi) For microemulsion formation
11 Autoclaving Autoclave (Thermo) For steam sterilization

Formulation development:
From the literature survey and understanding of the ophthalmic microemulsion, following types of the ingredients are required to form the stable microemulsion.
Table 2: Typical composition of ophthalmic microemulsion
Sr. No. Ingredient Class
1 Active Pharmaceutical ingradient
2 Drug solubilizing agent (Oil base)
3 Surfactant
4 Tonicity modifier
5 Viscosity modifier
6 pH adjustment agent
7 Vehicle
Critical quality product profile
Below table summarizes the quality attributes of ophthalmic emulsion and indicates which attributes were classified as drug product CQAs. For this product, physical attributes (e.g. pH, globules size distribution, viscosity, assay, related substances) are considered as critical. On the other hand, CQAs including identity, Osmolality, sterility which are unlikely to be impacted by formulation and process variables will not be discussed in detail in the pharmaceutical development report. However, these critical quality attributes (CQAs) are still target elements of the QTPP and are ensured through the product and process design and the control strategy.
Table 3: Quality attributes of ophthalmic emulsion
Drug Product Quality Attributes Target Criticality Justification
Description Homogenous emulsion Yes Non homogeneity of emulsion indicate the instability
Identification Positive for API No Both the formulation and process unlikely impact the identity
Assay 90-110% of label claim Yes Process may affect the assay value of the drug product
Degradation Product As per ICH No Based on the ICH limit.
Globule Size Distribution Z (Average ):
100-200 nm Yes Safety and efficacy of the emulsion dependent on the droplet size of the emulsion.
Physical stability of the dispersed system is directly dependent on the droplet size.
Viscosity 150 to 350 cps No Viscosity of the attributes of grade, concentration and type of polymer used in the product.
None of the process parameters will affect the viscosity of the emulsion formulation.
pH 6.5 to 8.0 No Not critical because, the desired pH is adjusted using suitable pH adjusting agent.
Osmolality 250-350 mOsml/kg No No change in the Osmolality value over the period of time
Sterility Must be sterile Yes Meet the requirement of sterile drug product

Pre-formulation studies:
Solubility study of the Drug: The solubility of Cyclosporine in various oils, surfactants and co-surfactants was determined. An excess amount of Cyclosporine was added to 5 ml of each selected oils and was shaken reciprocally at 25°C and 60°C for 24 hrs.
After solubilization at both the temperatures, drug solutions were kept at room temperature for 1 month to study physical stability.
Compatibility study with Surfactants: Polysorbate 80, Polysorbate 20 and Tyloxapol are the most used and approved surfactant in ophthalmic and injectable formulations. These were used for the compatibility study with the drug in 1:2 ratios. The drugs were dispersed in Polysorbate 80, Polysorbate 20 and Tyloxapol. These were kept at 25°C and 60°C for 7 days and checked for the physical observations.
Interaction study between oil solubilized API and surfactant: The interaction between solubilized drug in oil and the emulsion forming agent surfactant is very crucial for stability of the microemulsion. Cyclosporine was dissolved in the oils viz. castor oil, arachis oil, sesame oil and olive oil. All of oil solubilized drug solutions were mixed with different surfactant in 1:2 ratios. These mixtures were kept at 400C for 30 days.

Selection of Ingredients:
Selection and Optimization of Surfactant concentration: Compatibility studies were carried out using Polysorbate 80, Polysorbate 20 and Tyloxapol. Based on the compatibility studies, all surfactant were used for further stability studies with below concentrations,
Table 4: Surfactant concentrations for compatibility studies
Surfactants Surfactant concentration
Polysorbate 80 0.5 , 1.0 and 1.5 %
Polysorbate 20 0.5 , 1.0 and 1.5 %
Tyloxapol 0.5 , 1.0 and 1.5 %
Selection and Optimization of Viscosity modifier and Tonicity moodier:
1. Viscosity Modifier
Viscosity modifier is used in ophthalmic solutions to increase their viscosity. This enables the formulation to remain in the eye longer and gives more time for the drug to exert its therapeutic activity or undergo absorption. Carbomer 974P, hydroxyethylcellulose MX grade, carboxymethylcellulose sodium 7MFPH, viscosity modifier agents were used for the study.
Experiments were carried out using the all of the viscosity modifying and the below concentrations were used,
Table 5 : Concentrations of viscosity modifier
Viscosity modifier Concentration %w/v
Carbomer 974P 0.25 0.5 0.75
Hydroxyethylcellulose (MX) 0.25 0.5 0.75
Carboxymethylcellulose sodium 7MFPH 0.25 0.5 0.75
Purified water Q.S. to 40% Q.S. to 40% Q.S. to 40%

Above viscosity modifier agent (Polymer) was dispersed in 40% of the purified water. Tonicity modifier was dissolved in 40% of the purified water and autoclaved at 121?C for 15 min. The viscosity of the polymer solution was checked before and after the autoclaving.
Based on the autoclaved suitability and viscosity profile of polymer, Carbomer 974P and Hydroxyethylcellulose (MX) at a concentration of 0.75% and 0.25% respectively were selected as tonicity modifier for further studies.
2. Tonicity modifier
Based on the theoretical osmolality calculations below concentrations of tonicity modifier were used,
Table 6: Concentration of tonicity modifier
Viscosity modifier Tonicity modifier Concentration
Sodium Chloride 0.9%
Mannitol 5%
Glycerin 2.7%
Propylene Glycol 1.1%
Selection of optimized formula: Based on the experimental work carried to develop ophthalmic microemulsion, following formulae was selected for stability studies and complete evaluation.

Table 7 : Proposed final formula of the Cyclosporine ophthalmic microemulsion
Sl. No. Ingredients Formula A Formula B UOM
1 Cyclosporine 0.05 0.05 G
2 Castor oil 1.0 1.0 G
3 Polysorbate 80 1.0 1.0 G
4 Glycerin 2.70 2.70 G
5 Carbomer 974P 0.5 – G
6 Hydroxyethylcellulose(MX) – 0.25 G
7 Sodium hydroxide Q.S to pH Q.S to pH –
8 Hydrochloric acid Q.S to pH Q.S to pH –
9 Purified water Q.S. to 100mL Q.S. to 100mL –
Above formulations were prepared with the optimized process parameters and were tested for the all physicochemical parameters.

Microemulsion preparation
Studies were performed on a laboratory scale with batch sizes ranging from 100 mL to 1000 mL.
Cyclosporine was practically insoluble in purified water. Hence, the API is needed to dissolve oil under continuous stirring at elevated temperature. Once a clear solution is obtained, further processing is done.
The brief process is given as below,
1. Solubilization of drug in oil at elevated temperature.
2. Transfer sufficient quantity of purified water in the compounding vessel.
3. Add batch quantity of surfactant under continuous stirring.
4. Pre-mix the surfactant solution and oil phase using overhead/magnetic stirrer.
5. Set the high shear homogenizer at suitable parameters.
6. Transfer the API/ oil in the surfactant solution under continuous stirring and high shear homogenization.
7. Connect the High-pressure homogenizer with SS tank in the recirculation mode and continue homogenization of the emulsion at 50 to 80°C.
8. Continue the homogenization till the desired emulsion size attained.
9. Polymer phase was prepared by dispersing Viscosity modifier in sufficient quantity of purified water under continuous stirring.
10. Separately tonicity modifier is dissolved in sufficient quantity of purified water and added to the polymer phase from above step.
11. Check and adjust the pH of the emulsion and adjust if required with NaOH or HCl solutions.
12. Mix the above bulk emulsion
13. Filter and transfer the microemulsion from step 8 to polymer excipient phase from step 12 under stirring.
14. Make-up the volume of the batch to 100% of the batch size with purified water.
15. Mix the emulsion under slow continuous stirring for suitable period of time.
An outline of the manufacturing process unit operation is given in figure below,

Figure 2: Typical Manufacturing process flow for microemulsion

Process optimization:
High shear mixing: Emulsion stability is largely determined by droplet size; oil-in-water-emulsions having droplet sizes that exceed 1 ?m (coarse emulsion) in diameter tend to be less stable and undergo creaming, coagulation and phase separation upon storage. Therefore, it is desirable to reduce particle size during primary homogenization to less than 1µm. The aim of primary homogenization is to produce the emulsion droplets as small as possible. Primary homogenization was done by batch high shear homogenizer.
Crude emulsion was subjected to the high shear homogenizer at different temperature as below,
Table 8: Different temperature setting for high shear homogenizer
Trial No. Temperature Time in min RPM
C45 RT 10 2000
D46 400C 10 2000
C47 500C 10 2000
C48 600C 10 2000
C49 700C 10 2000
C50 800C 10 2000

Based on the above experiments, following temperature and different RPM setting of high shear homogenizer were evaluated,
Table 9: Different RPM setting for high shear homogenizer
Trial No. Temperature Time in min RPM
C51 60-700C 10 1000
C52 60-700C 10 2000
C53 60-700C 10 3000
High pressure homogenization: Objective of the high pressure homogenization is to achieve the desired droplet size of emulsion. At the end of primary emulsification, Panda, (Make: Gea Niro Soavi) which is a high pressure system (upto 30,000 psi) was used to reduce the droplet size of the disperse system. Primary emulsion was pumped through the interaction chamber at very high pressure, as the coarse emulsion passes through the valves; it experiences a combination of intense high shear and turbulent flow conditions. Internal force in turbulent flow along with cavitation is predominantly responsible for droplet size reduction in high pressure homogenizer. Reduction in the emulsion droplet size is a function of time.
Primary emulsion was subjected to different settings of high pressure homogenization as per the below parameters,
Table 10 : Different pressure setting for high pressure homogenizer
Trial Number C54 C55 C56
High Pressure Homogenization pressure 1000 Bar 1250 Bar 1500 Bar
Temperature 60-700C 60-700C 60-700C

Effect of temperature against the high pressure homogenization and following trials were carried,
Table 11 : Different temperature setting for high pressure homogenizer
Trial Number C57 C58 C55
High Pressure Homogenization pressure 1250 Bar 1250 Bar 1250 Bar
Temperature 25-350C 45-550C 60-700C

RESULTS
Process optimization:
High shear homogenization: The results of this process are given in the table below,
Table 12 : Effect of temperature on high shear homogenization
Temperature Time in min RPM Globule Size (Z Average) PDI
RT 10 2000 6488 nm 0.589
400C 10 2000 1763.8 nm 0.511
500C 10 2000 1471 nm 0.479
600C 10 2000 1102 nm 0.372
700C 10 2000 842.1 nm 0.329
800C 10 2000 673.4 nm 0.299

Table 13: Effect of RPM on high shear homogenization
Temperature Time in min RPM Globule Size (Z Average) PDI
60-700C 10 1000 8675.9 nm 0.876
60-700C 10 2000 935.9 nm 0.315
60-700C 10 3000 457.9 nm 0.245

Above results indicated that the temperature and time is having profound effect on the droplet size reduction of the oil in the emulsion.
During the primary emulsification (mixing of Castor-oil/API in the surfactant solution), coarse emulsion size less than (< 1µm) can be achieved by homogenization the emulsion for 10 minutes at 60 to 70°C.
High pressure homogenization: Primary emulsion was subjected to different setting of pressure for number of passes in high pressure homogenizer. The globule size reduction data is presented in the table below,

Table 14: Effect of different pressure setting on globule size reduction
Pass Number High pressure homogenizer pressure
C54 C55 C56
1000 Bar 1250 Bar 1500 Bar
Globule Size (nm) PDI Globule Size (nm) PDI Globule Size (nm) PDI
1 754.9 0.145 684.9 0.134 628.4 0.165
2 689.3 0.156 609.3 0.156 551.8 0.187
3 613.7 0.145 523.7 0.134 465.2 0.166
4 557.1 0.157 472.1 0.107 427.1 0.138
5 478.4 0.125 403.4 0.102 358.4 0.133
6 424.5 0.147 335.5 0.116 290.5 0.147
7 379.2 0.148 289.2 0.117 244.2 0.148
8 328.4 0.178 228.4 0.147 183.4 0.178
9 265.2 0.189 175.2 0.158 130.2 0.189
10 234.6 0.156 139.6 0.125 94.6 0.156
11 232.2 0.153 112.2 0.116 67.2 0.147
12 231.9 0.156 111.9 0.117 66.9 0.148
13 234.9 0.158 104.9 0.147 59.9 0.178
14 245.9 0.257 95.9 0.158 50.9 0.189

Above results indicate that the desired droplet size can be attained after 10 to 13 passes on high pressure homogenizer at a pressure of about 1250 . Further reduction in the droplet size is not significant. Hence on the bases of the above results it is concluded to run the secondary homogenization in the recirculation loop at least for 10 passes to achieve the desired droplet size.
Table 15: Effect of Temperature and pressure on microemulsion globule size
Trial Number C57 C58 C55
Pressure 1250 Bar 1250 Bar 1250 Bar
Temp. range 25-350C 45-550C 60-700C
No. of pass Globule Size (nm) PDI Globule Size (nm) PDI Globule Size (nm) PDI
1 984.7 0.364 864.9 0.268 684.9 0.134
2 908.4 0.311 790.3 0.313 609.3 0.156
3 821.8 0.269 705.5 0.292 523.7 0.134
4 769.1 0.213 655.9 0.262 472.1 0.107
5 699.4 0.203 587.5 0.248 403.4 0.102
6 630.7 0.231 520.3 0.262 335.5 0.116
7 583.2 0.233 475.1 0.251 289.2 0.117
8 521.9 0.293 415.6 0.271 228.4 0.147
9 467.2 0.315 363.8 0.274 175.2 0.158
10 430.7 0.249 328.4 0.241 139.6 0.125
11 402.5 0.231 302.9 0.231 112.2 0.116
12 401.7 0.233 302.2 0.232 111.9 0.117
13 400.4 0.293 299.8 0.253 104.9 0.147
14 403.7 0.315 300.5 0.259 95.9 0.158

Above results indicate that the desired droplet size reduction was more efficient with the increase in temperature during high pressure homogenization. Hence on the bases of the above results it is concluded to run the secondary homogenization at about 60-700C to achieve the desired droplet size.

Evaluation of formulations
Formulation were evaluated for different physicochemical parameter and the summary of results is presented in table below,
Table 16 : Summary of physicochemical parameters
Test Parameters Formula A Formula B
Description Opaque milky white viscous emulsion Opaque milky white viscous emulsion
pH 7.01 6.98
Osmolality (mOsmol/kg) 298 301
Viscosity (Cps) 209 347
Specific gravity 1.0012 1.0014
Globule size (Z avg nm) 112.9 114.3
PDI 0.175 0.189
Zeta potential (mV) -14.2 -12.7
Surface Tension (mN/m) 28.2 30.6
Assay (%) 100.1 99.6
In vitro Drug Release (Time in Hrs) % Drug Release
0 0 0
0.5 6.5 3.7
1 15.4 8.9
2 32.5 19.8
3 52.6 36.8
4 68.9 49.7
5 79.4 61.7
6 88.9 75.7
8 99.8 76.8
9 100.1 76.8

Based on the initial evaluation, it was observed that formulations with Hydroxyethylcellulose (MX), as a polymer was equivalent to formulations with Carbomer 974P except the in vitro drug release. Thus, formulations with Carbomer 974P were selected for the further stability studies.

Thermodynamic stability
Microemulsions are thermodynamically stable systems and are formed at a particular concentration of oil, surfactant and water, with no phase separation, creaming or cracking. It is the theremostability which differentiates microemulsion from coarse emulsions which have physical instability and will eventually phase separate. Thus, the selected formulations were subjected to different thermodynamic stability as below,
1. Heating-Cooling Cycle of 4?C and 45?C for 48Hrs
2. Freeze thaw cycle of – 21?C and +25 ?C for 48 Hrs

Table 17: Heating-Cooling Cycle and Freeze thaw cycle Cyclosporine ophthalmic emulsion
Condition Initial Heating-Cooling Cycle Freeze thaw cycle study
Cycle 1 Cycle 2 Cycle 1 Cycle 2
Description Opaque milky white viscous emulsion Opaque milky white viscous emulsion Opaque milky white viscous emulsion Opaque milky white viscous emulsion Opaque milky white viscous emulsion
pH 7.01 6.99 7.01 7 7.01
Osmolality (mOsmol/kg) 298 300 299 299 301
Globule size (Z avg nm) 112.9 113.1 114.2 112.6 111.9
PDI 0.175 0.181 0.183 0.179 0.181
Viscosity (Cps) 209 202 198 204 199
Assay (%) 100.1 100.3 98.4 100.3 98.4
Total Impurities (%) 0.89 0.87 0.91 0.87 0.91

Based on the above data, it was observed that microemulsions are thermodynamically stable systems as there was no significant change in physico-chemical parameters.

DISCUSSION
Description
Description of ophthalmic emulsion was observed as ”Opaque milky white viscous emulsion”. Milky appearance to the emulsion system, supposed to be due to presence of oil phase dispersed in water along with the surfactant. Opaqueness was observed due to the presence of viscosity modifier. Description of the ophthalmic emulsion was found to be unchanged during the stability studies.
pH
The excipients used in the formulation decide the pH of the final preparation. Change in pH may change zeta potential of formulation which in turn can affect the stability of preparation. So pH is also responsible for stability of microemulsion. All the formulations pH was adjusted to about 6.9 to 7.2 value. No pH shift was observed during the stability studies.
Osmolality
The osmolality of the prepared ophthalmic microemulsion was in the range of 290 to 320 mOsml/kg. No osmolality changes were observed during the stability studies.
Specific gravity
The specific gravity of the prepared ophthalmic microemulsion was in the range of 1.0000 to 1.0020. Specific gravity is not a stability indicating parameter, so no monitored during the stability.
Viscosity
Viscosity of microemulsion systems depends on viscosity modifier agent used and somewhat on the pH. The viscosity of the prepared ophthalmic microemulsion was in the range of 195 to 250 cps.
Surface tension
The surface tension values obtained for the microemulsion were in the range of 28.2 – 36.7 mN/m which is lower than the physiological value of the lachrymal fluid surface tension which ranges from 40 to 50 mN/m9. This result was expected because of the large amounts of surfactants used in the preparation of microemulsion. Administration of eye drops with lower surface tension than that of the lachrymal fluid resulted in destabilization of the tear film 10, 11. Film which can guarantee a good spreading effect on the cornea and mixing with the precorneal film constituents, thus possibly improving the contact between the drug and the corneal epithelium12.The low surface tension obtained for the developed microemulsion, thus, destabilized the tear and enhance the drug solubilization from the microemulsion.
Zeta potential
The droplet size of microemulsion is important criteria for evaluation and it should be less than 100 nm. Microemulsions with low droplet size are usually more stable compared with microemulsions with larger droplet size because larger droplets are more susceptible to aggregation or creaming. Zeta potential is related to surface charge of microemulsion droplet. The zeta potential governs the stability of Microemulsion. It is important to measure its value for stability samples. The high value of zeta potential indicates electrostatic repulsion between two droplets. DLVO theory states that electric double layer repulsion will stabilize microemulsion where electrolyte concentration in the continuous phase is less than a certain value. The theory states that system remains stable due to de-flocculation of microemulsion particles and for identical system zeta potential charge should be between ranges of -10 to -30 mV13.
Globule size
Globule size of oil droplet in microemulsion was determined by photon correlation spectroscopy that analyzes the fluctuations in light scattering due to Brownian motion of the particles using a Zetasizer (Nano-ZS, Malvern Instruments, UK). The formulation (0.1 mL) was dispersed in 50 mL of water in a volumetric flask, mixed thoroughly with vigorous shaking, and light scattering was monitored at 25°C at a 90°angle. Whereas zeta potential was measured using a disposable zeta cuvette. For each sample, the mean diameter/zeta potential ± standard deviation of three determinations was calculated applying multimodal analysis.
The globule size of the formulations was observed in the range of 100 to 120 nm and found to be similar during the stability studies.
Drug Content and Related substances
The drug content test was performed for the both the drugs. The amount of the Cyclosporine content in the selected formulations A and D was in the range of 98-101% of the added amount. The assay of Cyclosporine in ophthalmic microemulsion formulation revealed presence of the drug in the range of 98-99% in all formulations under the study. The results of assay revealed suitability of the system for high entrapment of drug in the internal phase.
Morphological characterization
Microscopic images of primary emulsion formed by the high shear homogenizer are given below. From the images, it was observed that uniform primary emulsion was formed by the high shear homogenizer.

Figure 3: Microscopic images of primary emulsion and TEM images of Cyclosporine ophthalmic microemulsion
TEM image of prepared microemulsion system of cyclosporine (Formula A) is shown below. It may be confirmed from the figure that uniform droplet size of the prepared system was observed.
Cyclosporine drug particles incorporated in oil droplet which was surrounded by water molecule. It confirms the formation of oil in water (o/w) microemulsion system.

In vitro drug release
Effect of Viscosity of emulsion: In vitro drug release for microemulsion with Carbomer and Hydroxyethylcellulose (MX), polymers is represented as graphical in below figure,
Based on this data, it is clear that, higher viscosity of the formulation retard the drug release, which can be correlated to the drug availability from the ophthalmic emulsion to the eye after instillation.

Figure 4: Graphical representation of in vitro drug release Cyclosporine ophthalmic emulsion
ACKNOWLEDGEMENT:
The authors are grateful to the authorities of Department of Pharmacy, Faculty of Allied Health Sciences, Mahatma Jyoti Rao Phoole University, Achrol, Jaipur, India for the facilities.

CONFLICT OF INTEREST:
The authors declare no conflict of interest.

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4. H. Sasaki, K. Yamamura, K. Nishida, J. Nakamura, M. Ichikawa, Delivery of drugs to the eye by topical application, Prog. Retin. Eye Res. 15 (1996) 583–620.
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9. Fialho SL, da Silva-Cunha A. New vehicle based on a microemulsion for topical ocular administration of dexamethasone. Clin Experiment Ophthalmol 2004;32:626-32
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Abstract:
Sociologists have been involved in an enduring debate as to whether social inequality based on class and that based on race intersect, in a Capitalist system. This paper aims to argue in favor of this proposition. The basis for this argument lies in the fact that since the global expansion of Capitalism has been made possible by a racist divide-and-conquer approach taken by the global elite since the mid-17th century.
Introduction:
Those who opine that social inequality based on race is merely a coincidence, tend to have their convictions rooted in their beliefs about the efficiency of capitalism; that capitalism rewards those who put the effort to make the best of their opportunities, in an unbiased market (Mania et. al, 2013). However, for most Marxist Sociologists, both racism and capitalism developed together, reinforcing one another in a single exploitative system. Capitalism, has great expansionary potential, for both economic growth and moving beyond national boundaries. These sociologists reckon that this very nature of capitalism stems from the need to expand into new markets, in search of raw materials, investment opportunities, and a cheaper labor (Lenin, 1917). Capitalism is a system created on the philosophy that humans are inherently greedy. Therefore, Capitalism at its highest stage is a manifestation of greed at its highest intensity.
To elaborate on this, we shall analyze Capitalism, in its infant stages as existing in free competition, where the forces of demand and supply determine the allocation of, and the need for, resources in an economy. All else being equal, this allocation of resources should be efficient, and everyone should be satisfied. However, as the scale through which capital governs the economy widens, all else is not equal- some people tend to be greedier than others. This inequality in the varying levels of greed is represented by a transition from free competition to monopoly. Thus, as Capitalism develops from cub to a mature predator, it is on the lookout for prey which it can devour.
Lenin defines Capitalism Imperialism as “a definite and very high stage of its development” which comes as “the replacement of capitalist free competition by capitalist monopoly”. The term “imperialism” was first used in the 1830s to recall Napoleonic ambitions. It gained its core contemporary meaning around the turn of the century as a description of the feverish colonial expansion of Britain, France, Germany, Russia, the United States, and Italy (Strang, 2001). This colonial expansion came not only from an economic need to expand, but also from the political rivalry that existed among some of these nations. Thus, ideology permeated the need for expansion.
European overseas expansion transitioned, crudely, from the colonial stage to the imperial. In the fifteenth and sixteenth centuries, seagoing powers constructed networks of colonial enclaves along the route to the East Indies. Less than fifty years after the voyages of Columbus, the conquistadors had decimated the Incan and Aztec empires and were sending gold and silver back to Spain (Strang, 2001). The Justifications for doing so came in colonial arguments that these people were “barbaric and uncivilized”, and that civilization needed to be brought to these “pagans”.
In the two hundred years following that, Spain, Portugal, Great Britain, France, and the Netherlands colonized virtually the whole of the Caribbean, Central and South America, and the North Atlantic seaboard (Strang, 2001).
Next, came the imperial stage of capitalism. According to Lenin (1917), the development of capitalist imperialism came with five features. The first was that the concentration of capital and production had developed into such a high stage that it played a significant role in socio-economic life. The second was that financial oligarchy was created by the merging of bank capital with financial capital. In other words, a select few, also known as the global elite, owned and the majority of wealth and therefore, the allocation of it. Third, the export of capital, man-made resources required for the production of even more wealth, gained more importance than the export of commodities. As a result of this came the fourth element, the formation of monopolist capitalist associations such as cartels, syndicates and trusts to create value for the elite. The aggregation of the aforementioned factors of imperialism inspired the fifth element: territorial division of the world amongst European powers, without the inclusion of any representatives from the divided territories (Lenin, 1917).
In the absence of an enforceable legal order, states are motivated to expand when possible or endure decline relative to more aggressive states (Strang, 2001). We shall focus on European imperialist expansion into Africa.
Slave trade, for centuries was Europe’s primary connection to Africa. Prisoners of war were sold to European Capitalists as slaves. These slaves possessed prowess in farming techniques and were a source of cheap labor for the European colonizers of the Americas. Since slaves could be easily and profitably obtained by the establishment of coastal slave castles, in collaboration with West African rulers, and trading centers, European slave traders saw no need to establish formal colonies in order to conduct their business (Bishop, 2013).
This extended period of a slavery-centered relationship between Europe and Africa strongly influenced European sensibilities toward Africans (Bishop, 2013). Africans were described as “primitive, static and asleep”. And so, the Europeans decided to take advantage of this and, ambush african states with maximum gun and breech loading rifles to make colonies of them. This came as a result of the miscalculations on the part of African leaders, in the faith they had in the Europeans for fair exchange, and that they were more technologically equipped and advanced than the Europeans they had encountered in the 15th century (Boahen, 1985).
We shall take a look developments of racist notions which people of European descent used to justify the rape of Africa during this period of Imperialism/ Colonialism.
In the United States, the coexistence of free labor in the North and slavery in the South, proved to be disastrous, drawing an especially harsh race line between blacks and whites. The very concept of whiteness became associated with the notion of freedom and free labor, while blacks were seen as naturally servile. White workers divided themselves from blacks (and other racially defined workers), believing that capitalists could use coerced and politically disabled workers to undermine their interests. Thus a deep division emerged in the working class, along racial lines. The racism of the white working class can be seen as a secondary phenomenon, arising from the ability of capitalists to engage in the super-exploitation of workers of color (Mania et. al, 2013) .
Although written at the end of the nineteenth century about Asia, Rudyard Kipling’s famous phrase “the White Man’s Burden,” also known as “the civilizing mission” in French and Portuguese, was an increasingly important impetus for imperial conquest in Africa throughout the nineteenth century as Europeans felt that Europe had a moral or religious obligation to bring civilization to those whom they perceived as uncivilized, pagan Africans (Bishop, 2013) . It helped pave the way for European imperialism at the end of the nineteenth century by establishing race as the basis for social distinctions, rights, and hierarchy, thus creating and maintaining an attitude of racial superiority that led to the dual vision of Africa as a barbarous land to be saved by Europe’s civilizing influence and as a geographic space without institutions, governments, or societies advanced enough to claim a place at the negotiating table during the Berlin Conference.

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