Intermacs classification with definitions and management strategies.
\r\n\tFrom a public health perspective, reduced health literacy can lead to widespread consequences. “Low health literacy is also costly for the country because when people don't understand health information and instructions, they are more likely to have worse health outcomes and unnecessarily use emergency room services,”. Experts agree that health literacy is vital to reducing healthcare costs and improving public health. The path to improving health literacy isn’t always straightforward, however.
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\r\n\t“Unfortunately, up to 9 out of 10 adults can have limited health literacy, and this can be fluid,” Blue says. “It can be more challenging to be health literate when we are sick or in pain, so even someone who normally has a high level of health literacy may struggle at times to understand and process health information.”
Heart failure (HF) is a common condition affecting 37.7 million people worldwide. In majority of affected patients it can be debilitating chronically if not immediately lethal in some. The burden on the affected individual as well as the wider society is considerable. Currently the best available treatment for worsening end-stage HF despite optimal medical therapy is considered to be heart transplantation with the caveat that it is available for only very few patients who are deemed eligible to be accepted on the waiting lists and survive long enough without precluding end-organ dysfunction for a suitable organ to become available. For the rest the outcome is very poor with an average survival of 50% at 5 years after diagnosis of HF, rates comparable with the diagnosis of cancer. While early extra-corporeal pulsatile mechanical circulatory support has been around since 1960s, it was the advent of continues flow intra-corporeal ventricular assist devices (VAD) that made this treatment widely available as longer term option to advanced HF patients. Last decade has seen a worldwide surge in the use of long-term left ventricular assist devices (LVAD) that has given a new hope to patients together with new challenges. These challenges are based around chronic driveline infections, right ventricular failure, neurological events and the dilemma between thrombosis and bleeding. Recently the focus of research and development has shifted towards alleviation of these complications and development of comprehensive strategies and pathways for acute and chronic HF patients.
\nHeart failure (HF) is one of the most common causes of death while it affects about 37.7 million people worldwide and was identified as an epidemic in 1997 [1, 2]. In majority of patients it can have a debilitating effect chronically if the initial insult is survived. The burden on the affected individual as well as the wider society is substantial. Poor exercise tolerance, chronic lethargy and depression with constant anxiety of sudden death together with frequent hospitalizations are among those factors limiting patients’ quality of life (QOL). The burden to the society is highlighted by 1–4% of all hospital admissions in Europe and US being due to HF with an average stay of 5–10 days and readmission rates of about 25% within 1 month and 50% within 2 months after discharge [3].
\nOver the last two decades the management of HF has improved with optimal medical therapy including ACE-Inhibitors, β-Blockers, loop-diuretics and Spironolactone together with implantable defibrillators and resynchronisation devices. However the best available therapy for advanced HF is heart transplantation with the caveat that it is available for only very few patients who are deemed eligible to be accepted on the waiting lists and survive long enough for a suitable organ to become available. For the rest the outcome is very poor with an average survival of 50% at 5 years and 10% at 10 years after diagnosis of HF. This rate has not changed in the last 20 years whereas the survival when diagnosed with cancer has doubled in the last 40 years. Therefore there is much potential for alternative treatment options of which the ventricular assist devices present a real hope.
\nThe relative short history of mechanical circulatory support in clinical use started with the invention of the cardiopulmonary bypass machine early 1950s that allowed safe operations on the open heart. The first device to temporarily support the circulation other than for heart operations was reported in 1962 in the form of intra-aortic balloon pump (IABP) [4, 5]. The research into the development of more substantial mechanical circulatory assist devices that was initiated by the National Institutes of Health (NIH) in the US was responsible for most of the progress that followed from the 1960s onwards. Funded by the NIH we had the first reported clinical use of an intra-corporeal and then extra-corporeal ventricular assist devices in 1963 and 1966 respectively by DeBakey’s group [6]. A total artificial heart (TAH) was developed in Baylor College of Medicine and then implanted in 1969 by Cooley. Much progress in the following 30 years has been around sizeable extra-corporeal devices that were driven pneumatically with substantial consoles. These were relatively successful so-called first generation short-term devices with pulsatile flow pattern allowing patients in acute heart failure to bridge to recovery or transplantation but were burdened with high rates of mortality and morbidity. Patients were bed-bound, unable to mobilise and could only be supported for few days to weeks. The lack of long-term durability of these devices was the main factor to restrict the use only as a short-term bridge to transplantation.
\nThe next big step towards more usable devices took shape around the millennium with a new so called second generation devices that were smaller therefor implantable and intracorporeal. These pumps provided a continues flow (CF) pattern generated by an axial rotor which was suspended mechanically in its casing. The lack of pulse was a shock to the medical community that required some debate and time to get over. These CF VADs also required thinner drivelines that helped to reduce the infections often originating from exit sites of large cannula and drive lines of the first generation devices. To date the most commonly used example of these devices is the HeartMate II which is still used frequently. Other rarely used examples were Jarvik 2000 and Micromed DeBakey VAD.
\nAnother quantum leap happened more recently in the last decade when there was a surge in the number of implanted LVAD’s worldwide triggered by both the new licences obtained for destination therapies and particularly with further progress achieved with newer so called third generation devices. These devices introduced substantial progress in further miniaturisation, reliability, durability and noise reduction all of which contributed to the usability and long-term manageability of patients who now tend to envisage living with these devices for the rest of their lives. Primary third generation device example is the HeartWare HVAD with recent addition of HeartMate 3 both of which have a centrifugal pump that is magnetically suspended eliminating wear-out with better durability. Miniaturisation meant that they could be implanted entirely intra-pericardial even on smaller adults and children.
\nCurrent research focuses in reducing the much feared morbidities. Driveline infections is one and often cited as the ‘Achilles’ tendon’ of LVADs. Progress in transcutaneous energy transmission systems (TETS) promise to avoid the need for drivelines altogether. Special consideration of the right ventricle (RV) is required as the vast majority of VADs is placed for the support of the left ventricle with early and late post-operative RV failure resulting in significant increase in mortality. Strategies have been developed to predict RV failure, to preventively optimise haemodynamic parameters pre-operatively and to improve management post-operatively. The dilemma between pump thrombosis and bleeding can be very difficult to manage and has to be patient specific. Usual long-term strategy involves a combination of warfarinisation and anti-platelet therapy that allows individual attention to patients’ tendency to either “bleed” or “clot”. Another fascinating area of research is gastro-intestinal AV-malformations and their relationship with von Willebrand factor and CF pattern of these new devices. Newer materials are sought for better biocompatibility and reduced thrombogenic properties.
\nDue to the unique nature of patients and their LVADs most of established MCS Programs have now comprehensive long-term management protocols involving patients’ families, General Practitioners, local emergency departments and hospitals, ambulance services and local government services.
\nThe vast majority of currently used LVADs are the HeartWare HVAD and HeartMate 3. Both are miniaturised and fully implantable into the pericardial cavity and by the use of a centrifugal pump that is magnetically levitated they avoid mechanical wear-out therefore more durable and less thrombogenic. The HVAD has a centrifugal pump that is magnetically levitated with hydrodynamic bearings avoiding mechanical interface resulting with only one moving part that is the pump which is driven by two motors providing a continuous flows of blood. The HVAD System weighs at 160 g and is small enough to fit intra-pericardial in most patients with dilated cardiomyopathy. There have been reports of two pumps for bi-ventricular support and some paediatric use to ages below 10 years all of which placed fully intra-pericardial [7, 8, 9]. Only some restrictive cardiomyopathy and smaller children present a challenge due to lack of intra-pericardial space. The HeartMate 3 is similar in design and function with certain differences. These include full magnetic levitation without hydrodynamic bearings allowing for the rotor to operate in wider RPM ranges which in turn allows flows between 2.5 and 10.0 L/min and larger gaps between the rotor and the casing reducing the haemolysis and sheer stress to the blood. There is also an attempt to address the concerns about CF in regards to its causative effects on AVM’s by incorporating a degree of pulsatility to the flow profile. The Abiomed Impella device is a different approach which includes the option of percutaneous insertion and placement across the aortic valve with blood inlet area in the LV cavity and outlet area in the ascending aorta reaching flows up to 5 L/min. An axial rotor is positioned at the outlet area. Common complications include haemolysis, device thrombosis, bleeding, vascular injury and arrhythmia [10, 11]. There are numerous other short- and long-term ventricular assist devices available however these are less frequently used by the majority of centres specialising in MCS.
\nEach patient in heart failure requires individualised assessment for suitability for MCS implantation which proposes only one aspect of patient management. Patient and device choice depend on the indication and purpose of the MCS implantation. Statistically over the last decade the majority of patients treated with assist devices fall in to Intermacs classes 1–4. Table 1 describing severity of heart failure according Intermacs classification (Interagency Registry for Mechanically Assisted Circulatory Support) and expected survival of patients in each category which helps to determine the urgency of the intervention as well as its type.
\nIntermacs level | \nShort code | \nDefinition | \nExpected survival: action required | \n
---|---|---|---|
Level 1 | \n“Crash-and-burn” | \nCritical cardiogenic shock, oliguria/anuria, rising lactate levels and liver function tests | \nHours/days: immediate intervention required | \n
Level 2 | \n“Sliding fast” | \nProgressive decline despite inotropic support | \nDays/weeks: intervention within days | \n
Level 3 | \n“Hospital bound” | \nStable but inotrope dependent | \nWeeks/months: elective MCS vs. Transplant within weeks | \n
Level 4 | \n“Frequent flyer” | \nResting symptoms, frequent hospitalisation with decompensation | \nMonths/year: elective MCS vs. Transplant | \n
Level 5 | \n“House bound” | \nComfortable at rest, intolerant to minimal activity of daily living | \nYear/s: elective MCS vs. transplant depends on other parameters | \n
Level 6 | \n“Walking wounded” | \nExertion intolerant, can only manage normal activity of daily living | \nYear/s: elective MCS vs. transplant depends on other parameters | \n
Level 7 | \nNYHA III | \nAdvanced NYHA III | \nYears: medical management, MCS or transplant not indicated | \n
Intermacs classification with definitions and management strategies.
Level 1: patients in this category usually present with fulminant myocarditis or more commonly after complicated myocardial infarction when primary PCI failed to restore the resulting acute loss of pump function of the heart. If there is sufficient evidence that the individual would be suitable transplant candidate than a longer term MCS could be considered but in reality in this emergency setting this evidence is lacking so that in most cases short-term MCS device is chosen as salvage and bridge to decision. Devices to consider for these patients include intra-aortic-balloon-pump (IABP), extra-corporeal-membrane-oxygenator (ECMO) or more recently the Impella device or TandemHeart. While the application of ECMO usually requires a dedicated centre, the insertion and management of IABP or Impella is less cumbersome but only provide partial support of the circulation. Occasionally the Impella device is also used for right ventricular support either in addition to the left sided support or in isolation. There are reports from highly specialised ECMO centres achieving relatively high survival rates for ECMO application on patients with out-of-hospital-cardiac-arrest (OOHCA) and ongoing CPR [12].
\nLevel 2: these patients are deteriorating despite escalating inotropic support and usually show end-organ dysfunction and not expected to survive more than days or weeks. They are either unfit for transplantation due to end-organ dysfunction or not expected to survive long enough for a suitable donor-heart to become available. Considerations for Level 2 patents include destination therapy or bridge to either decision or candidacy/transplantation. Devices for this category include HVAD or HM3 among other less often used devices as well as even less commonly used total artificial heart systems (TAH). More common than TAH is the temporary support of the right ventricle with extra-corporeal CentriMag in addition to an LVAD. If there is complicating respiratory dysfunction, it is easy to add an oxygenator to the CentriMag circuit and await recovery.
\nLevel 3 and 4: these patients have a very poor quality of life being either hospital bound or admitted frequently. They also often have end-organ dysfunction that precludes them from listing for transplantation. If they are suitable for transplantation and have preferable blood group/typing and body weight and if the geographical donor pool is preferable making heart transplantation likely within few weeks or months then waiting for transplantation may be a good option. However in reality in most centres in the world overcoming all of these postulations and receive a successful heart transplantation is preserved to a very few lucky ones. In vast majority patients at this level of disease progression present considerable disease burden and require MCS in an elective fashion. Left ventricular support with HVAD and HM3 are most commonly used. In patients with concomitant right ventricular dysfunction there are different approaches available. Mostly, pre- and post-operative optimisation and attentive management of the body fluid equilibrium are sufficient to prevent right ventricular failure. Sometimes a temporary RVAD with CentriMag is required to overcome the immediate intra- and post-operative insult to the right ventricle. A right sided Impella is also an option in this setting.
\nLevel 5 and 6: patients at these levels of disease progression are usually stable in the short and medium term period therefore could be placed on heart transplant waiting lists with close follow up to early pick up any sign of deterioration or end-organ dysfunction. Some patients in this category present or develop pulmonary hypertension precluding them from listing for transplantation which can be improved with an LVAD therapy rendering them into a candidacy position. Generally these patients are not considered for MCS as the heart failure burden is comparable with the burden of any type of mechanical support is often accompanied. In the coming years this cohort of patients will become increasingly the focus when we can significantly reduce the frequently observed complications related to MCS.
\nEnd-stage heart failure with diminished organ perfusion has a detrimental effect to most of organ systems of the body. Renal dysfunction due to reduced cardiac output, liver dysfunction due to cardiac output as well as congestion, nutritional depletion due to dysfunctional gastrointestinal absorption as well as liver dysfunction causing physical debilitation, respiratory dysfunction due to congestion as well as pulmonary hypertension, upwards regulation of the systemic inflammatory responses, cognitive impairment due to hypoxia and psychological implications due to constant anxiety and burden of the disease all contribute to push the individual into a vicious circle and downwards spiral of end-stage heart failure. Any MCS system aiming to alleviate the underlying cardiac dysfunction is bound to fail if these organ systems are not concomitantly addressed.
\nAggressive fluid removal with high dosages of loop-diuretics and/or renal replacement therapy in form of haemofiltration may be required on top of optimal medical therapy which includes β-Blockers, ACE-Inhibitors and Spironolactone. The achievement of the ideal fluid equilibrium sets the right ventricle in a best possible starting position to overcome the strains of the operation and the increased cardiac output that will be provided by the LVAD. The use of infused phosphodiesterase inhibitors and inhaled nitric oxide can support the right ventricle in this immediate post-operative period. Cardiac arrhythmia needs to be treated aggressively for the same purpose.
\nIntensive input from the dietitian as well as physiotherapist and psychologist represent cornerstones of optimal pre- and post-operative management of patients receiving MCS.
\nThe urgency of the procedure and the type of MCS together with the individual clinicians and units experience determines the technique of implantation. Of course there are different approaches to the implantation technique including bilateral small thoracotomies, avoidance of the CPB, using more distal aortic sites for outflow-graft anastomosis and exit point of the drive-line. We will however only discuss the most common approaches of the techniques related to the implantation of the most commonly used devices.
\nThe simple percutaneous insertion of IABP does not require much attention due to its common use and familiarity. The Impella device is inserted percutaneously through the femoral or subclavian/axillary arteries with the help of Fluoroscopy and cardiac catheterisation techniques. The blood inlet area is at the tip of the device which is positioned across the aortic valve in the left ventricular outflow tract well away above the papillary muscles and the outlet area is positioned well above the aortic valve at the level of the sino-tubular junction. Trans-oesophageal Echocardiographic images help exactly position the inlet and outlet areas.
\nFor the implantation of the HVAD the patient is positioned supine and draped exposing the entire front of the trunk including cranially the jugular notch and medial two thirds of the clavicles for the exposure of the subclavian vessels, laterally along the anterior axillary line down to the anterior superior iliac spinosus and further down the lateral thigh and caudally just above the patella. The groins are kept prepared in case femoral cannulation is required for ECMO or additional RVAD support. Standard median sternotomy and ascending aortic and right atrial cannulation is performed for cardiopulmonary bypass (CPB). Techniques avoiding median sternotomy therefor avoiding the need for re-do sternotomy for eventual heart transplantation includes left anterior thoracotomy at the apex which can be localised with TTE, and right parasternal thoracotomy at 2nd ICS can be used with or without CPB. The LV apex is examined and the dimple identified to centre the sewing ring around just lateral to the distal LAD. We use 16 pledged 4/0 Prolene sutures in a horizontal mattress fashion and a layer of sealant to secure the sewing ring in position. Then while the heart is fibrillated a cross incision with a blade is made and the coring device provided in the implantation pack is used to remove a cylindric piece of myocardium within the sewing ring. The HVAD device is then inserted into the sewing ring and fastened with the screw driver provided. The inflow cannula is oriented directly pointing to the middle of the mitral valve which is confirmed with TOE images. The outflow graft is left open momentarily for de-airing. The outflow graft is then sutured with continues 5/0 Prolene sutures just like any other top-end anastomosis right laterally onto the ascending aorta above the ST junction and above the SVC using a side-biting clamp. The clamp on the graft can again be released momentarily before tying the knot for further de-airing of the LV. The driveline can now be tunnelled across the abdominal wall with three exit points in a Z-shaped or V-shaped course initially sub-fascial then subcutaneous. The final exit point is at the level lateral and below the umbilicus either on the right or the left flank depending on patients’ handedness and preference which is usually determined pre-operatively if possible. After the driveline is connected to the driver CPB is discontinued slowly and the HVAD started and RPMs set that allow the inter-ventricular septum to be straight and neither bulged to the left nor to the right. TOE is used to assess the septum as well as right ventricular function and aortic valve opening. Volume load, inotropic support, especially Milrinone, inhaled nitric oxide and setting of the RPMs of the LVAD can help to fine tune the patients’ haemodynamic equilibrium and prevent RV failure. This is usually the timing for the decision to add an RVAD is made. The implantation of the HM3 is very similar with that of the HVAD with only little differences owing to the design of the pump.
\nIf there is the need for temporary RVAD then CentriMag is often used as extracorporeal centrifugal VAD using the femoral venous cannulation for inflow and a Gore-Tex vascular graft onto the pulmonary artery and tunnelled through the left second intercostal space parasternally and above the pectoral muscle with any aortic cannula attached as outflow. If a more long-term RVAD is required then another HVAD can be used in intra-pericardial position using inferior RV wall or the RA as inflow access and the PA as outflow. The use of TAH could also be considered however the evidence for long-term TAH is scanty.
\nWe will investigate not the common complications related to any heart surgery but only those particular to VADs. These include drive-line infections (DLI), pump thrombosis (PT), GI-bleeding, cerebral vascular incidents, right ventricular failure and aortic valve insufficiency.
\nOverall DLI incidence is around 10–20% with higher rates observed with devices requiring a pump-pocket or has larger diameter drivelines [13]. This rate is also dependent on patient and procedure risk factors including hygiene, nutritional status, diabetes, urgency of the procedure and implantation technique. Prolonged subcutaneous course is thought to prevent speedy up-migration of potential DLI towards the pump itself with severe consequences however at the same time it increases the potential infection sites by increasing the number of skin breakages to allow the long course. The use of antibiotic containing products deposited at the exit site may also help reduce the infection rate. The burial of the Dacron part of the DL below the skin allowing only silicone-skin interface as well as perpendicular exit of the DL as supposed to lying on the skin can further help reduce the DLI rates. Treatment includes targeted antimicrobial therapy and surgical exploration with debridement and re-routing of the DL. Long-term suppressive antimicrobial therapy is a not too unfeasible option to control and contain infections that are difficult to eradicate or too close to the pump and carry high risk for operative approach.
\nPatients present with different levels of general coagulability, which is why there are rather non-scientific terms like “
Surveillance of anticoagulation is routinely done by INR measurements complemented by platelet count and serum LDH. However some centres advocate more detailed assessments including platelet function tests, anti-Xa levels and thromboelastogram (TEG).
\nThe diagnosis of pump thrombosis is suspected primarily if there is increase in pump power with or without pump flow changes. This is due to the fact that the driver has to spend more power to achieve same speed of the rotor which is impeded by the presence of the thrombus either reducing the blood inflow into the cannula or through the pump or the outflow graft or indeed mechanically impeding the rotation of the rotor inside the pump in areas of the rotor bearings. Further diagnostic test is the serum LDH levels which increase relative to baseline surveillance levels. Clinical signs i.e. haematuria, of or laboratory tests for haemolysis the likes of haptoglobin, plasma-free haemoglobin, bilirubin and fibrinolysis products can aid the diagnosis. If the pump thrombosis is large enough to cause reduction of pump output signs of heart failure can resurface. Cardiac imaging with Echocardiogram and/or CT Thorax for visualisation of the thrombus in the ventricular cavity as well as assessment of ventricular filling together with manipulation of the pump speed can be carried out for further differentiate the diagnosis.
\nTreatment of device thrombosis depends on the severity of the thrombus and its haemodynamic and device related complications. This would include up-regulation of anticoagulation, intravenous heparinisation, systemic thrombolysis or device exchange if the former interventions are not successful. New approaches with intra-ventricular and/or intra-pump thrombolysis and washout are being assessed for safety and effectiveness.
\nIntractable epistaxis is mentioned but not further discussed here as often this can be managed successfully with the input of ENT Surgeons. There are several reports and studies investigating bleeding from the entire gastro-intestinal tract (GIT). Obvious predisposing risk factors include reflux oesophagitis, gastritis or inflammatory diseases like Crohn’s or Colitis which may present themselves as contraindication for VAD therapy as they will be very difficult if not impossible to manage with full anticoagulation. More intriguing concept in continues flow (CF) LVAD therapy is the often encountered arteriovenous-malformations (AVM) that seems to be associated with von Willebrand factor (vWF) deficiency. There are theoretical and conceptual suggestions that the continues flow pattern of these devices are at least partially responsible for development of AVM’s in the GIT. Simultaneously the accelerated speed of the blood through the rotors of these CF pumps is said to be responsible for high shear forces active on the high molecular weight vWF causing distortions/breakages leading to qualitative changes with subsequent reduction of function in relation to platelet aggregation. This combination of AVM’s with vWF deficiency gives rise to intractable bleeding occasionally leading to surgical intervention.
\nIntracerebral events are feared for the reason that they are often fatal. They can be of two sometime overlapping pathophysiology namely embolic or haemorrhagic of nature. Embolic events are more often encountered peri-operatively due to particulate matter or air from the operative field reaching cerebral vasculature causing ischaemia. The particulate emboli can originate from preexisting thrombi from the LV or LA cavity, atherosclerotic debris from the aortic manipulation during cross clamping or graft anastomosis or paradoxical thrombi crossing across an undiagnosed ASD. Therefore great care is taken in pre-operative workup to identify these risk factors. Air emboli can be avoided with appropriate and assiduous de-airing manoeuvres aided by CO2 insufflation of the operative cavity. Later in the follow up period haemorrhagic intracerebral events predominate in frequency and lethality although often overlapped with embolic events that transform into haemorrhagic lesions.
\nManagement of the right ventricle in patients receiving LVADs can present itself like a manoeuvre ‘between Scylla and Charybdis’. Bi-ventricular assist device implantation has reportedly high mortality therefore efforts are focused into avoidance of RVAD in addition to LVAD therapy if at all possible [14, 15, 16, 17]. Strategies have been developed over the last decade that include optimisation of hydrostatic status of the heart failure patients including oral and intravenous pharmacological as well as renal replacement therapies. This effort aims to set the right ventricular filling pressures into the optimal position on the Frank-Starling Curve with the best possible contractility resulting from the actin-myosin relationship. In practice this means to aim to decrease the central venous pressure down to single figures i.e. below 10 mmHg prior to the procedure if there is sufficient time available. Further fluid can be removed using haemofiltration during cardiopulmonary bypass if used. Other peri-operative measures include off-pump and minimally invasive techniques to minimise systemic inflammatory response to the procedure, TOE guided optimisation of the position of the ventricular septum by manipulation of the LVAD speed and the use of pulmonary arterial pressure attenuating pharmacology including intravenous phosphodiesterase inhibitors and inhaled nitric oxide. Comprehensive heart rhythm management including resynchronisation and anti-arrhythmic strategies are required to avoid the undesirable effects of arrhythmia to RV function. Hybrid approaches of endocardial and epicardial ablation for supra-ventricular or ventricular arrhythmias may represent a feasible option in some centres. Continued effort is necessary in the long-term follow up of these patients focussing on hydrostatic optimisation if the right ventricular function is to be kept under control.
\nThe evidence is mounting that show the adverse effect of the continues flow LVADS to the aortic valve [18, 19, 20, 21, 22]. Constant closure of the valve during LVAD support encourages fusion of the leaflets leading to stenosis. More importantly the lack of physiological movements of the leaflets during the cardiac cycle leads to worsening of mild to moderate regurgitation with increased morbidity. Over time an increasing portion of the pump flow returns back to the LV cavity creating a short circuit with resulting peripheral hypo-perfusion and LV filling pressures consequently return of heart failure symptoms. Manipulation of pump speeds to achieve sufficient aortic valve opening is proposed by large MCS Centres. Bioprosthetic aortic valve replacement for more than mild aortic regurgitation at the time of LVAD implantation has been advocated by experts more frequently in recent years.
\nThe patient population with long-term LVAD therapy has been increasing due to the improved technology and the management strategies of the complications. More patients are now receiving LVADs as de-facto destination therapy as there is no other promising treatment option available for patients who do not belong to the lucky few transplant recipients. This increasing population require close and continued care that is very distinct and individualised. A great number of regional health care services, social services and potentially family and friends need to be involved in the care of these patients. Local emergency services and hospitals need to be familiarised with the specific patient profiles. They need not to panic and commence CPR if there is no pulse. They need to know that some arrhythmia is better tolerated than without an LVAD, that deranged anticoagulation does not always require immediate counter measures, that any infection/sepsis can have amplified detrimental effects on RV function and anticoagulation and that their hydrostatic equilibrium may have a very small margin of safety. Social services and local council authorities have to facilitate emergency measure for power cuts. Relatives and friends or carers need to familiarise themselves with the LVAD driver connections to the drive-line, batteries and power cables and what certain alarms mean and how to contact the appropriate MCS Centre. This close monitoring and cooperation can only be achieved with dedicated VAD coordinators taking on a central role between the patient and their carers, the clinicians and local emergency and social services. Well thought through protocols taking into account the geographic particularities and circumstances are required to accommodate the needs of this distinct group of patients that is certain to grow in numbers in the not so far future.
\nThe technology around mechanical circulatory support is evolving with an exponential speed which makes any prediction beyond few years futile. We can however look into current work that is focusing in the alleviation of VAD complications and is promising to become clinical practice in foreseeable future. One of these is contactless energy transfer that is combined with subcutaneous implantable batteries allowing transcutaneous energy transfer (TET) and avoid the driveline passing through the skin eliminating the ‘Achilles’ heel’ of MCS Systems [23]. Further work involves strategies aiming for early and more sensitive recognition and treatment of certain complications especially the likes of pump thrombosis. These techniques use remote monitoring systems with in-time assessment and intervention of pump readings and parameters to more finely tune the VAD therapy [24]. Improved biocompatibility of materials used and rotor design will surely be helpful to reduce thrombosis risk as well as to reduce shear forces affecting blood components. Further miniaturisation and less invasive techniques of implantation can be expected to become more common place in the near future and will allow to expand the age spectrum of the recipients. Better understanding and management of right ventricular dysfunction may be coupled with more intuitive bi-ventricular support in order to achieve better and sustainable results. With improved results and better control of complications one can expect to broaden the spectrum of recipients to less sick patients and include Intermacs classes 5 and above to preemptively avoid end-organ dysfunction of heart failure patients.
\nWithin a relatively short period of emergence the implantation of left ventricular assist devices have made a huge impact in treatment of end-stage heart failure patients. The development of a new treatment method inevitably brings with it new challenges that limit its spectrum of utilisation. LVAD specific challenges which represent the limiting factors are mainly driveline infections, anticoagulation balances, cerebral incidents and right ventricular dysfunction. We can be optimistic that current research will lead to progress in tackling of these challenges so that we will be able to claim that this therapy method represents a first line management plan for HF patients. Notwithstanding the recent encouraging attempts of widening the donor pool to donation after circulatory death, the number of heart transplantation worldwide has reached a plateau and is only available to very few select types of patients. The prospect of much improved mechanical support methods for the circulation with better manageability represents a real hope for patients in wider age spectrum as well as in earlier phases of disease progression. Sooner or later MCS Systems that are available off the shelf and adaptable to each patients needs have the potential to replace heart transplantation for end-stage heart failure. However we may want to mention here that in parallel there are endeavours in bioengineering and gene-manipulation which could allow speculations into the ‘off-the-shelf’ availability of authentic spare organs for each person.
\nThe authors have no conflicts of interest to declare.
Oral drug delivery is the most used route in the pharmaceutical industry. Over 80 percent of drugs are formulated in solid state, not only because of the advantages referred to noninvasive administration and medication adherence but also for reasons of stability from manipulation and storage of unprocessed material to the drug development process [1, 2, 3]. Generally, solid drugs are more chemically stable in the solid state than in solution, where degradation occurs more easily [4]. However, despite the oral delivery potential in comparison with other routes, the oral absorption mechanism of drugs is more complex and requires adequate solubility and stability values in the different portions of the gastrointestinal tract, as well as appropriate dissolution profiles [3]. Furthermore, the numerous structural possibilities of a particular active pharmaceutical ingredient (API) in the solid state, as well as several pharmaceutical production parameters, can have a considerable impact on its chemical, physical, and biopharmaceutical properties [1, 5].
In this context, the aim of solid screening is to select the optimal form with the best characteristics for development. This chapter will go through some of the most important aspects of the API study in solid state.
A drug can exist in different solid forms, including crystalline and amorphous materials, which are classified into single-component systems and multicomponent systems. In addition, each crystal form may crystallize in many different forms, a property known as polymorphism. Polymorphism can be defined as the ability of a molecule to crystallize in multiple crystal structures with identical chemist composition but different molecular packing, and in some cases, also different conformation [6, 7]. Its study is critical in pharmacy because more than 80% of drugs exhibit this phenomenon in which different polymorphs of the same API may have different properties, affecting the viability, safety, shelf life, solubility, dissolution, stability, toxicity, and bioavailability of oral formulations [8].
Single-component systems include anhydrous or non-solvated drugs. These drugs may have multiple polymorph forms, each of which is identified by a different number (roman or arabic). Ritonavir is a historic case involving problems of dissolution and bioavailability in commercialized drugs associated with a polymorphic transformation of form I to form II, which is more stable but less soluble [9]. Other drugs with polymorphic anhydrous forms include sulfathiazole [10], carbamazepine [11], paracetamol [12], fluconazole [13], among others.
On the other hand, the multicomponent crystal systems comprise drug molecules that have different intermolecular interactions with other molecules (guest molecule or coformer) or ion, resulting in the formation of a new solid form without alterations in the covalent chemistry [7, 14, 15]. This group is formed by solvates, hydrates, co-crystals, salts, and a combination of these (like salt hydrates, salt solvates, co-crystal solvates, co-crystal salt, and co-crystal salt solvates) [14, 16, 17, 18, 19, 20]. In addition, each multi-component system may have polymorphs [21]. The multicomponent systems can modify different properties of the API without changing its molecular structure, resulting in improved solubility, dissolution, and bioavailability, among others benefits [15].
Solvates are systems in which the drug molecule and the solvent molecule are trapped in the crystalline lattice interacting via hydrogen bonds (mainly). When the solvent molecule is water the system is called hydrate. Crystal hydrates can exist in stoichiometric relations (monohydrate, dihydrate, etc.) or non-stoichiometric relations [22]. The role of the solvate or water molecule can be as a guest or as a stabilizer of the crystal structure [23]. Some examples of solvents used for forming solvates are dimethyl sulfoxide, ethanol, dimethylformamide, ethyl acetate, acetone, and others [24].
Co-crystals are formed by a neutral drug molecule and a co-crystal former in stoichiometry relation [15, 25]. Both molecules reside in the same crystal lattice and are bonding through non-covalent interactions. In particular, hydrogen bonds are especially important in co-crystals but dipolar, π-stacking, van der Waals and halogen-hydrogen interactions may also stabilize the crystalline structure [6, 14, 15]. The selection of co-crystal formers is based on the functional groups of the API, so molecular recognition is favored by using complementary functional groups. Examples of co-crystal formers are acids, amides, carbohydrates, alcohols, and amino acids [26].
Salts are formed by strong ionic interaction of drug molecules with other molecules or atoms ionized, which act like an oppositely charged counterion. Therefore, the ionizable groups of the API limited its formation [23]. In addition, other interactions can act cooperatively to stabilize the crystal form like hydrogen bonding or coordination interactions [14]. The “pKa rule” is an accepted method used in the salt formation that uses the difference between pKa values of API and coformer to predict their behavior. The salt formation is possible if ΔpKa (ΔpKa = pKabase - pKaacid) is less than 3 [15].
In order to guarantee the API solid form present in the bulk material and its pharmaceutical formulations it is critical to evaluate and characterize each solid form, this topic will be detailed in Section 4.
As mentioned in the previous section, there exist numerous types of pharmaceutical solid forms in the crystalline state (polymorph, solvate/hydrate, co-crystal, salt). Crystals are solids with a regular array of atoms and molecules built from a translational repetition of the basic structure denominated by unit cell. Thereby, a complete description of the concept of crystallization is fundamental.
Crystallization is a phenomenon that occurs as a result of two different processes. The first is called nucleation, which is the beginning of a phase transition from a supersaturated state that gives rise to the appearance of a small nucleus in a second phase. The second one is the crystal growth process, which involves the evolution layer by layer to determine the crystal packing of the unit cell [27]. The strength of the intermolecular interactions within the unit cell is what determines which layers dominate the crystal growth process [28]. Therefore, the crystals of an API can differ in size relative to the growth of particular faces and the number and type of faces present, ergo they can have different crystal habits, which characterizes the crystal shape (acicular, prismatic, pyramidal, tabular, columnar or lamellar type).
Crystallization is a process of transformation from a solution or melt to the crystalline state. The generation of crystal nuclei is controlled by the crystallization conditions (e.g., solvent, temperature, and supersaturations). Moreover, a solvent or additive in the process of growth may cause competition for a site at an incoming point associated with the layer-by-layer growth process that would be capable of disrupting the magnitude of the intermolecular interactions generating inhibition or interference in the growth directions which is manifest as a change in the overall morphology of the crystal. In industrial crystallization, seeding the supersaturated solution with crystalline material is a common strategy for ensuring batch-to-batch reproducibility and optimizing process robustness by controlling the whole crystallization process by minimizing spontaneous nucleation. In particular, the addition of desired form seeds is the technique most used to control polymorphism [27].
The crystallization process was described using a variety of methodologies (summarized in Figure 1), each with its own characteristic, including crystallization from a single solvent, evaporation from a binary mixture of solvents, antisolvent addition, temperature gradient, vapor diffusion, slurrying, and liquid assisted grinding [4, 6, 15]. The crystallization from a solution could proceed in different ways, including slow cooling of a hot saturated solution, slow warming, or by heating the solution to boiling and then quenching cool using an ice bath. On the other hand, if crystallization from a solution is not possible, there are a number of processes that do not require the use of a solvent such as sublimation, thermal treatment, crystallization from the melt, neat grinding, capillary crystallization, laser-induced crystallization and sono-crystallization [27, 29].
Methodologies for manufacturing solid pharmaceutical materials.
The techniques applied for the preparation can use thermodynamic or kinetic conditions, depending on whether the thermodynamic equilibrium is maintained or the situation moves away from equilibrium, respectively, to obtain the crystallization of different crystal forms. The synthesis mechanisms that obtain thermodynamic conditions include slow evaporation, and slow cooling, among others. While kinetic conditions refer to high supersaturation degree, quench cooling, and rapid solvent evaporation, among others [30]. Under stress situations, crystallization kinetics will control the crystal shape, rather than thermodynamics conditions, and the production of more unstable solid forms will be favored kinetically [6].
Additionally, the initial phases of crystallization, determined by the time between supersaturation and the development of nuclei, are critical in regulating the characteristics of the final solid phase, such as purity, crystal structure, and particle size [27]. In general, the most thermodynamically stable crystalline form is preferable. Crystallization performed in close proximity to equilibrium are likely to generate forms of relatively stable or ground-state polymorphs. Though the production of amorphous or metastable forms with increased solubility and dissolution rates may be favored by bioavailability requirements [6]. For example, techniques that produce an abrupt change in the system, such as sublimation or crystallization from the melt, result in a metastable solid form. Thermal desolvation of crystalline solvates can generate amorphous materials, with the solvent contributing to stabilizing the lattice. While techniques such as quench cooling can also be used to obtain amorphous forms. However, these high-energy forms tend to be transformed into a stable form through a solid-solid physical transition, a phase transformation with solvent mediation, or both.
As previously mentioned, changes in the properties of solids can occur during pharmaceutical drug manufacturing and storage. Normally, drugs are manufactured in a stable crystalline form because the risk of solid state transformations during storage is minimized. However, when developing a solid crystalline form, a rigorous control must be made to determine if the crystalline form is maintained or if there were changes during its production [31].
Currently, there are a variety of techniques to characterize a crystal. Characterization techniques are valuable tools that make it possible to determine the structure, chemical composition, and different properties of a pharmaceutical sample. However, simply one technique will not be able to offer complete information for a solid substance. It is vital to utilize them in a complementary manner in order to acquire acceptable outcomes (Figure 2). The most important techniques used in the pharmaceutical field for crystal characterization are those described below.
A) Powder X-ray diffraction patterns and B) Fourier-transform infrared spectra of a) furosemide form I, b) furosemide form II, c) oxytetracycline hydrochloride form I, d) oxytetracycline hydrochloride form II, and e) oxytetracycline hydrochloride form III.
Thermal analytical methods, which offer information on the thermal behavior of materials, are widely utilized in the physical characterization of pharmaceutical solids. When a sample is exposed to a temperature increase, the observed changes in characteristics can be measured [32, 33]. The thermal methods most commonly applied in the analysis of pharmaceutical solids are differential scanning calorimetry and thermogravimetric analysis.
This technique provides information about the physical and energetic properties of a substance subjected to temperature variations. To obtain a DSC thermogram, the difference in heat flux of a sample as a function of temperature or time is measured. Typically, this study is performed by comparing the thermogram of a sample of interest, such as a crystal, to that of a reference sample. The deviation in the thermogram below the reference corresponds to an endothermic transition, while the deviation above the reference relates to an exothermic transition [34]. The curve obtained can be used to determine enthalpies of crystal fusion, phase transition temperatures, purity, degree of crystallinity, type of interaction between molecules, and thermal stability [34, 35].
Numerous studies reported the most popular application of DSC in the field of pharmaceuticals. Their application in the characterization of polymorphic drugs such as albendazole and clarithromycin can be seen in Figure 3A. The representative DSC curve for albendazole form I exhibits a fusion endotherm, whereas the profile for form II shows a preceding endo-exothermic event that indicates its polymorphic transformation to form I, followed by an endotherm attributed to form I melting, and lastly an exotherm of decomposition. Similarly, the profile for clarithromycin form 0 exhibits an exotherm corresponding to a solid phase transition, followed by an endotherm assigned to the form II melting event due to its coincidence with the melting endotherm evidenced in the clarithromycin form II DSC curve.
A) Differential scanning calorimetry curves of a) albendazole form I, b) albendazole form II, c) clarithromycin form II, d) clarithromycin form 0 and B) thermogravimetric curves of a) oxytetracycline hydrochloride form I, b) oxytetracycline hydrochloride form II, c) clarithromycin form 0, d) clarithromycin form II.
TGA measures the mass change of a sample as a function of temperature or heating time. It is a simple technique that requires a smaller sample size [36]. A thermogravimetric curve shows the mass change due to physical and chemical phenomena such as absorption, melting, sublimation, vaporization, oxidation, reduction, and decomposition events [32].
It is a useful tool to quantify different processes such as crystalline melting, sublimation, or decomposition of a sample, and to elucidate the degree of purity of the API [37]. On the other hand, it is possible to elucidate on the curves, whether the crystals under study contain water or a solvent [36]. Moreover, it allows the detection of solvent loss in a crystal. For instance, information on dehydration/desolvation events for clarithromycin and oxytetracycline hydrochloride polymorphs was obtained (Figure 3B), as demonstrated by a mass loss at low temperatures in the TGA profiles. When the TGA profiles of Clarithromycin form 0 and form II are compared, it is clear that form 0 is a solvate, as demonstrated by the weight loss caused by the ethanol evaporation process. On the other hand, TGA profiles of oxytetracycline hydrochloride form I showed a larger mass loss until 100°C than those of form II, indicating variations in solid dehydration. These TGA curves also revealed that form II had higher thermal stability.
The technique most commonly utilized for identifying and characterizing crystalline materials is X-ray diffraction. Differentiating between crystalline and amorphous forms, identifying distinct solid forms of crystals, defining the crystalline structure of the API, and analyzing the differences between different crystal forms are some of its applications. As a result, it is commonly used in the pharmaceutical field [36]. For example, X-ray diffraction experiments have provided an unequivocal identification of furosemide and oxytetracycline hydrochloride polymorphs (Figure 2A), which exhibited clear differences in terms of reflection positions and relative intensity.
Single crystal X-ray diffraction is employed to determine the molecular structure of pharmaceutical materials that exist as single crystals [7, 38, 39]. A three-dimensional picture of the molecule and geometrical properties data in the solid state can be produced by studying a perfectly crystalline sample [40]. Powder X-ray diffraction is applied when the crystalline material is found as a fine-grained powder, rather than a single crystal [7, 38, 39, 41].
Vibrational spectroscopic techniques are widely used in the pharmaceutical field to identify crystalline solids due are fast, non-destructive, and can characterize solid samples with minimal or no preparation. The most commonly used methods for analyzing crystalline samples are Fourier-transform infrared (FT-IR) and Raman spectroscopy [7, 31].
These techniques are extensively utilized in the study of pharmaceutical solids to characterize amorphous and crystalline phases, identify the structure and composition of different pharmaceutical solid forms, determine the compatibility of mixtures, and establish molecular interactions [42].
For instance, FT-IR spectroscopy has been used in several studies to identify the individual polymorphic forms of a drug confirming that they are structurally distinct. Differences in characteristic FT-IR bands assigned to sulphonamide NH and secondary amine NH stretches were identified between furosemide polymorphs (Figure 2B). In the same way, significant differences between oxytetracycline hydrochloride polymorphs were observed in the bands attributed to the OH and amide NH stretching vibrations (Figure 2B).
ssNMR is a non-destructive and multinuclear technique that exploits the magnetic properties of certain nuclei, for example, 1H, 13C, 15N, 17O, and 19F. Although it is a non-routinary expensive methodology that has extensive experimental times and robust expertise users are required, it is widely used in pharmaceutical applications [32].
This technique is used to analyze crystalline and amorphous pharmaceutical samples qualitatively and quantitatively, as well as to characterize both APIs and formulations. Structural or dynamic information is obtained from mono and bidimensional experiments based on different nuclear interactions. Their pharmaceutical applications included identification, characterization, and quantitation of different solid forms of an API in bulk samples; determination of conformational and crystalline packing behavior, intra- and intermolecular interactions, internuclear distances; study of amorphous phase properties, stability of API forms, the effects of drug processing, molecular motions, chemical and physical interactions between API-excipient and excipient-excipient, solid state chemical reactivity; and identification of contaminants or degradation products, among others [7, 43, 44].
Microscopy is considered a tool of great interest in the pharmaceutical field, which is mainly used to examine shape and size and to identify the solid state form in the sample. Different types of microscopes are currently used for the characterization of pharmaceutical crystals [32, 45]. The most relevant are described below.
SEM is a very useful and versatile tool in the pharmaceutical field. It provides quantitative as well as qualitative information such as morphology, size, size distribution, crystal shape, and consistency of powders or compressed dosage forms by analyzing the images obtained by microscopy. In addition, it allows studying the effects of any interaction with its environment [7, 45].
Microscopic analysis of pharmaceutical crystals using SEM microphotographs reveals significant morphological differences between solids produced using distinct crystallization techniques, allowing each polymorphic form of the drug to be identified. In Figure 4, for example, significant differences in particle size and shape can be observed. Albendazole form I appear as small and irregular particles with a predisposition to aggregate while in contrast albendazole form II exhibits self-agglomerate lamellar particles with a smooth surface. Furosemide form I presented hexagonal and tubular compact crystals with a defined surface while furosemide form II shows fine and elongated prism particles. On the other hand, a compact structure with small particles adhered to the surface is observed for norfloxacin form BI, while the norfloxacin form C crystals are typical hexagonal-like faceted, compact, and with well-defined smooth structures. Finally, oxytetracycline hydrochloride form I have particles with a smooth surface and well-defined edges, form II crystals show compact particles with an irregular surface, form III presents rod-shaped crystals with a smooth surface with defined edges, while the form IV appeared as thin agglomerated needles.
SEM images of the morphology of a) abendazole form I, b) albendazole form II, c) furosemide form I, d) furosemide form II, e) norfloxacin form BI, f) norfloxacin form C, g) oxytetracycline hydrochloride form I, h) oxytetracycline hydrochloride form III, i) oxytetracycline hydrochloride form II, and j) oxytetracycline hydrochloride form IV.
An optical microscope is used to observe crystals directly providing information on particle size and shape. In addition, the nucleation events can be visualized by monitoring within situ cameras [32].
The utilization of polarized light, on the other hand, optimizes the utility of optical microscopes. Using polarized light microscopy, the interior structure of crystals can be analyzed and determined if the sample is amorphous or crystalline. Due to birefringence, several colors can be seen in a crystalline particle when viewed through crossed polarizers [7, 32, 45].
For example, significant differences in particle size and shape of sulphathiazole precipitated from a variety of solvents and techniques between them and compared additionally with commercial sulphathiazole can be observed by an optical microscope. In addition, these different sulphathiazole crystal forms exhibit different birefringence under a polarized light microscope. Figure 5 shows images of commercial sulphathiazole (Figure 5a and b) and samples obtained by the crystallization of commercial sulphathiazole from methanol heating the solution below the boiling point to the total solution (Figure 5c and d), from aqueous solution heating below the boiling point to total solution and immediately cooled at freezer temperature (Figure 5e and f), and from the saturated aqueous solution obtained below 80°C that was exposed to a temperature ramp of 90 to 25°C for one hour and then kept at 25°C for 24 hours (Figure 5g and h), 1hour (Figure 5i and j) and 30 minutes (Figure 5k and l).
a), c), e), g), i) and k) images obtained using an optical microscope. b), d), f), h), j) and l) images obtained using a polarized light microscope.
As described above, the crystallization process determines different habit crystals associated with particular lattice energy, resulting in measurable differences in physical properties. Therefore, different crystalline forms of a drug can be used in pharmaceutical science to improve their physicochemical and biopharmaceutical properties such as melting point, hygroscopicity, solubility, dissolution rate, stability (physical and chemical) mechanical and optical properties. The wettability of an API, for example, has an impact on its solubilization and dissolution processes. The absorption rate of many poorly soluble drugs is determined by their dissolution rate. Hence, drug molecules with poor solubility may lead to slow dissolution in biological fluids, resulting in an erratic bioavailability and consequent sub-optimal efficacy when delivered via the oral route [28, 30, 46].
The crystal morphology of solid drugs influences their dissolving rate due to critical factors such as surface area, size, and even the polymorphic form of the material, which may have a potential impact on the rate and extent of drug absorption.
The size of drug particles and their ability to be wetted by gastrointestinal fluids determine the drug surface area accessible for dissolution. The particle size is dependent on the crystallization conditions or on milling procedures. Therefore, controlled crystallization methods must be used to produce powders with high purity and predetermined particle size distribution for API administration.
The effect of crystal form on the dissolution and bioavailability of the API has been demonstrated. The kinetic transformation and growth conditions in crystallization have a direct effect to generate a particular architecture, which can be a stable polymorph or a metastable form. The polymorph selection process requires a high level of manipulation and control to obtain specific crystal structures grown in selected solvents.
In general, different polymorphs show solubility differences typically smaller than 10 times due to relative differences in free energy. Some examples include the evaluation of solubility, in aqueous and buffer solutions, of several forms of furosemide [47], norfloxacin [48, 49, 50], albendazole [51], and oxytetracycline hydrochloride [52]. These studies demonstrate that the molecular arrangement of each polymorphic form and its degree of ionization has a considerable impact on drug solubility (Table 1).
Solution | Furosemide (ug/mL)a | Norfloxacin (mg/mL)a | Albendazole (ug/mL)b | Oxytetracycline hydrochloride (mg/mL)b |
---|---|---|---|---|
Aqueous | Form I: 35.6 Form II: 27.4 | Form A: 0.32 Form BI: 0.30 Form C: 0.29 | Form I: 1.2 Form II: 2.8 | Form I: 91 Form II: 6.8 Form III: 6.7 |
Simulated gastric fluid | Form I: 4.4 Form II: 6.1 | Form I: 183 Form II: 320 | Form I: 93 Form II: FS Form III: FS | |
Simulated intestinal fluid | Form I: 3.3 Form II: 7.1 | Form I: 76 Form II: 1.20 Form III: 0.91 | ||
Buffer pH 6.0 | Form A: 0.39 Form BI:1.40 Form C: 2.61 | |||
Buffer pH 8.0 | Form A: 0.18 Form BI: 0.60 Form C: 1.38 |
Influence of crystal form on drug solubility.
Solubility at 25.0 ± 0.1°C.
Solubility at 37.0 ± 0.1°C, FS: freely soluble.
Additionally, the effect of polymorphs on bioavailability has a direct impact on pharmacokinetic parameters. A typical example is chloramphenicol palmitate, which exists in 4 solid forms: A, B, C and amorphous structure. Form A is the most stable, however, only the metastable form B and the amorphous solid have biological activity. Aguiar [53] reported that the blood serum level of form B is substantially higher than form A, by nearly an order of magnitude, after oral administration of suspensions at the same dose. It was concluded that form B has high free energy, then is more soluble and thus has a higher rate of absorption and bioavailability.
In some situations, occasionally metastable crystalline or amorphous forms are utilized for drugs orally administered if a faster dissolution rate or higher concentration is desired, in order to achieve rapid absorption and therapeutic effectiveness. Although metastable polymorphs can improve solubility, dissolution, and bioavailability, they can also be transformed into a more thermodynamically stable form during manufacture and storage, which results in unacceptable bioavailability and limits their potential performance. As an example, the polymorphic transformation of chlorpropamide caused by the mechanical energy of tableting compression was described. The heat generated by the compaction process would accelerate the transformation process of the metastable form C into the stable form A, in consequence, its dissolution rate decreases after compression [54, 55].
Furthermore, physical form stability in the gastrointestinal environment should also be considered. During gastrointestinal transit, the transformation in the most stable form is a relevant factor to consider. If the conversion occurs in the course of oral administration, a less soluble form will precipitate reducing oral absorption. For example, Kobayashi [56] demonstrated some differences in the oral pharmacokinetics and bioavailability between carbamazepine polymorphs (anhydrous forms I and III) and the dihydrate form. The plasma concentration-time profiles of polymorphs and dihydrate form differ in correlation with their dissolution profiles, which were in the order form III \\form I\\dihydrate; furthermore, form III was transformed in situ to dihydrate form faster than form I. By comparing the in vivo performance of carbamazepine at high doses, the form I provide better pharmacokinetic parameters than the other two forms. The inconsistency between the order of initial dissolution rates and pharmacokinetics values suggested a probable rapid transformation of form III to the dihydrate form in the gastrointestinal fluids, resulting in a slowing of dissolution due to the production of the dihydrate form.
A substantial solubility difference between amorphous and crystalline API is observed. The high-energy amorphous solids significantly enhance the solubility of poorly soluble drugs as compared to crystalline forms, resulting in a faster dissolution rate and subsequent oral absorption, which are linked to their metastable nature. In the dry state, the amorphous solid is typically more reactive than the crystalline form due to its higher thermodynamic activity. Furthermore, if exposed to humid conditions, amorphous solids become more hygroscopic, and the absorbed moisture works as a plasticizer, resulting in a substantial increase in molecular mobility. As a result, the chemical stability of an amorphous material is significantly lower than that of the crystalline phase when exposed to moisture. On the other hand, these metastable phases are susceptible to phase transformation during storage, which limits their application in pharmaceutical dosage forms. Although physical and chemical stability of amorphous phases is a major concern, if these high-energy forms can be stabilized to prevent crystallization over their intended storage life using excipients of conventional solid dosage formulation, these solids can be a useful tool for increasing API dissolution in biological fluids given bioavailability enhancement. For example, Yang [57] compared the bioavailability of amorphous and crystalline itraconazole nanoparticles administered via pulmonary. It was observed that amorphous nanoparticulate itraconazole had a rapid dissolution that produced a significantly higher systemic bioavailability than crystalline nanoparticles due to its supersaturation 4.7-times larger, which increased the drug permeation and will be thus beneficial for both local and systemic therapy.
Crystal engineering of co-crystals is another alternative formulation for improving drug attributes including solubility, dissolution, bioavailability, and physical stability of poorly soluble API. The modification of the physicochemical properties of the API and bulk material while maintaining the intrinsic activity of the drug molecule is enabled by co-crystallization during dosage form design [28, 58]. Several examples of API co-crystals with pharmaceutically approved coformers can be found in the literature. Screening for obtaining the optimal solid form is critical in co-crystal development, given the risks and high development industrial costs, because not every co-crystal may significantly enhance the solubility and dissolution rate of the API. A typical example is the carbamazepine-nicotinamide co-crystal that spontaneously converts to carbamazepine dehydrate during dissolution, which has a lower solubility, and the theoretical solubility/dissolution improvement of the co-crystal cannot be obtained [59]. Similarly, co-crystals of efavirenz were developed using several coformers [60]. When compared to pure efavirenz, efavirenz-DL-alanine and efavirenz-oxalic acid co-crystals had higher solubility and enhanced dissolution profiles, while efavirenz-maleic acid and efavirenz-nicotinamide co-crystals had decreased dissolution.
The salt formation has been used to improve the bioavailability since the solubilities of salts are typically higher. Changing the counterions in a salt varies its solubility and dissolution rate, affecting bioavailability, pharmacokinetic profile, and potential toxicity. Also, the salt will impact the chemical stability. Different microenvironmental pH and different molecular patterns in a specific lattice are factors that contribute to the difference between salt and its unionized form or between different salts. Recently, multi-drug salts of norfloxacin have been obtained with diclofenac, diflunisal, and mefenamic acid, as well as norfloxacin salt hydrate with indomethacin. Among them, norfloxacin salts with diflunisal and indomethacin showed higher solubility and permeability and hence increased bioavailability [61].
Understanding the characteristics of APIs in the solid state is critical in the field of pharmaceutical sciences since it is the basis for controlling the pharmaceutical performance of final formulations. In order to obtain solid pharmaceutical materials with improved properties, the crystal engineering strategy is used. Different crystallization processes are the experimental key to the solid form screening aiming to select the suitable physical form of a drug. As discussed above, the change in crystal form may not only affect the stability and mechanical attributes of the solid but, more importantly, may compromise the drug absorption through a change in solubility. In practice, is desirable that the drug’s physical form does not change during its manufacture and storage life to prevent a significant impact on its quality and bioavailability. Therefore, the characterization of the API solid phases such as polymorphs, solvates, hydrates, salts, co-crystals, and amorphous forms is critical in the early stages of the solid form development as well as a tool for evaluating the influences of manufacturing processes and storage on phase transitions as important factors for product quality assurance.
The authors declare no conflict of interest.
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At the beginning of humification, the significant decrease in the intensity of the band located at 1735 cm–1 shows that lignin is affected at the first stage of the composting process. At the end of the humification, the band located toward 3450–3420 cm–1 at the beginning of the process undergoes a systematic shift (Δν of the order of 10 cm–1) toward lower wave numbers. The band located at 1660–1650 cm–1 on the Fourier transform infrared spectroscopy (FTIR) spectra before composting shifts systematically toward 1640 cm–1 at the end of humification. This phenomenon can be used as index of compost maturity. Measuring the band at 1035 cm–1 as an internal standard, it is possible to quantify the degradation rate of organic matter.",book:{id:"4645",slug:"biodegradation-and-bioremediation-of-polluted-systems-new-advances-and-technologies",title:"Biodegradation and Bioremediation of Polluted Systems",fullTitle:"Biodegradation and Bioremediation of Polluted Systems - New Advances and Technologies"},signatures:"Loubna El Fels, Mohamed Zamama and Mohamed Hafidi",authors:[{id:"164092",title:"Prof.",name:"Mohamed",middleName:null,surname:"Hafidi",slug:"mohamed-hafidi",fullName:"Mohamed Hafidi"},{id:"175610",title:"Dr.",name:"Loubna",middleName:null,surname:"El Fels",slug:"loubna-el-fels",fullName:"Loubna El Fels"},{id:"175611",title:"Prof.",name:"Mohamed",middleName:null,surname:"Zamama",slug:"mohamed-zamama",fullName:"Mohamed Zamama"}]}],mostDownloadedChaptersLast30Days:[{id:"42059",title:"Adsorption Technique for the Removal of Organic Pollutants from Water and Wastewater",slug:"adsorption-technique-for-the-removal-of-organic-pollutants-from-water-and-wastewater",totalDownloads:29962,totalCrossrefCites:51,totalDimensionsCites:210,abstract:null,book:{id:"3426",slug:"organic-pollutants-monitoring-risk-and-treatment",title:"Organic Pollutants",fullTitle:"Organic Pollutants - Monitoring, Risk and Treatment"},signatures:"Mohamed Nageeb Rashed",authors:[{id:"63465",title:"Prof.",name:"Mohamed Nageeb",middleName:null,surname:"Rashed",slug:"mohamed-nageeb-rashed",fullName:"Mohamed Nageeb Rashed"}]},{id:"42294",title:"The Investigation and Assessment on Groundwater Organic Pollution",slug:"the-investigation-and-assessment-on-groundwater-organic-pollution",totalDownloads:4384,totalCrossrefCites:4,totalDimensionsCites:5,abstract:null,book:{id:"3426",slug:"organic-pollutants-monitoring-risk-and-treatment",title:"Organic Pollutants",fullTitle:"Organic Pollutants - Monitoring, Risk and Treatment"},signatures:"Hongqi Wang, Shuyuan Liu and Shasha Du",authors:[{id:"161340",title:"Prof.",name:"Hongqi",middleName:null,surname:"Wang",slug:"hongqi-wang",fullName:"Hongqi Wang"}]},{id:"77370",title:"Conventional and Contemporary Techniques for Removal of Heavy Metals from Soil",slug:"conventional-and-contemporary-techniques-for-removal-of-heavy-metals-from-soil",totalDownloads:213,totalCrossrefCites:0,totalDimensionsCites:1,abstract:"One of the most important components of the natural environment is soil. Soil is a non-renewable natural resources on which the whole human society is dependent for various goods and services. The intensive, and unsustainable anthropogenic practices along with the rapid growth of the human population have led to continuous expansion and concern for the degradation of soil. The agricultural soil is exposed to a plethora of contaminants, the most significant contaminant among them is heavy metals. The major sources of heavy metal contamination are associated with agriculture, industries, and mining. The increase of heavy metal contents in the soil system affects all organisms via biomagnification. In this chapter, we will review various conventional and contemporary physical or chemical and biological techniques for remediation of contaminated soil. 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PAHs are considered hazardous because of cytotoxic, mutagenic, and carcinogenic effects. Sixteen individual PAH compounds have been identified as priority pollutants by the United States Environmental Protection Agency (U.S. EPA). All substances originated in to the environment by either biogenic or anthropogenic sources. Anthropogenic compounds describe synthetic compounds, and compound classes as well as elements and naturally occurring chemical entities which are mobilized by man’s activities. In the marine environment, the fate of pollutants is largely determined by biogeochemical process. Some of these chemical changes enhance the toxicity of the pollutants. Other chemical changes cause the degradation or immobilization of pollutants and, as a result, act to purify the waters. Possible fates for PAHs, released into the environment, include volatilization, photo-oxidation, chemical oxidation, bioaccumulation and adsorption on soil particles, leaching, and microbial degradation. 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Serves as a peer reviewer for biomedical journals. 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From 1964 to 1974, he worked as an Assistant in Biochemistry at the School of Medicine at the same university. From 1974 to 1976, he was a fellow of the National Institutes of Health (NIH) at the University of Connecticut, Health Center, USA. From 1985 to 2004, he served as a Full Professor of Biochemistry at the Universidad Nacional de La Plata. He is a member of the National Research Council (CONICET), Argentina, and the Argentine Society for Biochemistry and Molecular Biology (SAIB). His laboratory has been interested for many years in the lipid peroxidation of biological membranes from various tissues and different species. Dr. Catalá has directed twelve doctoral theses, published more than 100 papers in peer-reviewed journals, several chapters in books, and edited twelve books. He received awards at the 40th International Conference Biochemistry of Lipids 1999 in Dijon, France. He is the winner of the Bimbo Pan-American Nutrition, Food Science and Technology Award 2006 and 2012, South America, Human Nutrition, Professional Category. In 2006, he won the Bernardo Houssay award in pharmacology, in recognition of his meritorious works of research. Dr. Catalá belongs to the editorial board of several journals including Journal of Lipids; International Review of Biophysical Chemistry; Frontiers in Membrane Physiology and Biophysics; World Journal of Experimental Medicine and Biochemistry Research International; World Journal of Biological Chemistry, Diabetes, and the Pancreas; International Journal of Chronic Diseases & Therapy; and International Journal of Nutrition. He is the co-editor of The Open Biology Journal and associate editor for Oxidative Medicine and Cellular Longevity.",institutionString:"Universidad Nacional de La Plata",institution:{name:"National University of La Plata",institutionURL:null,country:{name:"Argentina"}}}]},{type:"book",id:"6924",title:"Adenosine Triphosphate in Health and Disease",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/6924.jpg",slug:"adenosine-triphosphate-in-health-and-disease",publishedDate:"April 24th 2019",editedByType:"Edited by",bookSignature:"Gyula Mozsik",hash:"04106c232a3c68fec07ba7cf00d2522d",volumeInSeries:3,fullTitle:"Adenosine Triphosphate in Health and Disease",editors:[{id:"58390",title:"Dr.",name:"Gyula",middleName:null,surname:"Mozsik",slug:"gyula-mozsik",fullName:"Gyula Mozsik",profilePictureURL:"https://mts.intechopen.com/storage/users/58390/images/system/58390.png",biography:"Gyula Mózsik MD, Ph.D., ScD (med), is an emeritus professor of Medicine at the First Department of Medicine, Univesity of Pécs, Hungary. 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Thus proteomics, an area of research that detects all protein forms expressed in an organism, including splice isoforms and post-translational modifications, is more suitable than genomics for a comprehensive understanding of the biochemical processes that govern life. The most common proteomics applications are currently in the clinical field for the identification, in a variety of biological matrices, of biomarkers for diagnosis and therapeutic intervention of disorders. From the comparison of proteomic profiles of control and disease or different physiological states, which may emerge, changes in protein expression can provide new insights into the roles played by some proteins in human pathologies. Understanding how proteins function and interact with each other is another goal of proteomics that makes this approach even more intriguing. Specialized technology and expertise are required to assess the proteome of any biological sample. Currently, proteomics relies mainly on mass spectrometry (MS) combined with electrophoretic (1 or 2-DE-MS) and/or chromatographic techniques (LC-MS/MS). MS is an excellent tool that has gained popularity in proteomics because of its ability to gather a complex body of information such as cataloging protein expression, identifying protein modification sites, and defining protein interactions. 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